> ## Documentation Index
> Fetch the complete documentation index at: https://proto.evodesign.org/docs/llms.txt
> Use this file to discover all available pages before exploring further.

# AlphaMissense DB

> AlphaMissense is a Google DeepMind model that predicts the pathogenicity of every possible missense substitution for the human proteome, precomputed and served as static CSV files by the AlphaFold Protein Structure Database. The `alphamissense-db-fetch` tool retrieves the full per-substitution prediction set for one human UniProt accession, returning each substitution's pathogenicity score in `[0, 1]`, its classification (`likely_benign`, `ambiguous`, or `likely_pathogenic`), the prediction count, and the mean pathogenicity. It runs on CPU and requires only network access.

<div class="page-hero"><img class="page-hero-banner" src="https://proto-bio.github.io/proto-assets/images/tool/alphamissense_db/hero.png" alt="AlphaMissense DB" /><div class="tool-org-badges page-hero-badges"><a href="/docs/tools/organizations/google-deepmind" class="tool-org-badge" style={{background: "#1a237e"}} title="Google DeepMind"><img src="https://mintcdn.com/bio-pro/_UGa2jUMKeVPCbLk/assets/images/cached/170f4f446634.png?fit=max&auto=format&n=_UGa2jUMKeVPCbLk&q=85&s=c925c2862540b2476392ff2a71a0dba8" alt="" class="tool-org-badge-logo" width="200" height="200" data-path="assets/images/cached/170f4f446634.png" /> Google DeepMind</a></div></div>

<Note>
  **License:** AlphaMissense DB retrieves data from the AlphaFold Protein Structure Database, distributed under CC-BY-4.0. Attribution to the AlphaFold Protein Structure Database is required when the data is redistributed. The client wrapper code is MIT-licensed. Please refer to [the data terms](https://alphafold.ebi.ac.uk/faq) for full terms.
</Note>

<p class="entity-disclaimer">Proto is not affiliated with Google DeepMind. This toolkit is open source and builds on the implementation produced by this organization. Product names, logos, and trademarks are the property of their respective owners.</p>

<hr class="entity-rule" />

<input type="radio" name="tab-alphamissense-db" id="none-alphamissense-db" class="tab-radio-input" />

<input type="radio" name="tab-alphamissense-db" id="github-alphamissense-db" class="tab-radio-input" defaultChecked />

<input type="radio" name="tab-alphamissense-db" id="paper-alphamissense-db" class="tab-radio-input" />

<input type="radio" name="tab-alphamissense-db" id="cite-alphamissense-db" class="tab-radio-input" />

<input type="radio" name="tab-alphamissense-db" id="source-alphamissense-db" class="tab-radio-input" />

<input type="radio" name="tab-alphamissense-db" id="notebook-alphamissense-db" class="tab-radio-input" />

<input type="radio" name="tab-alphamissense-db" id="proto-alphamissense-db" class="tab-radio-input" />

<div class="tool-tab-bar">
  <span class="tool-tab-wrap"><label for="github-alphamissense-db" class="tool-tab tab-open badge-github"><svg width="14" height="14" viewBox="0 0 24 24" fill="currentColor"><path d="M12 0C5.37 0 0 5.37 0 12c0 5.31 3.435 9.795 8.205 11.385.6.105.825-.255.825-.57 0-.285-.015-1.23-.015-2.235-3.015.555-3.795-.735-4.035-1.41-.135-.345-.72-1.41-1.23-1.695-.42-.225-1.02-.78-.015-.795.945-.015 1.62.87 1.845 1.23 1.08 1.815 2.805 1.305 3.495.99.105-.78.42-1.305.765-1.605-2.67-.3-5.46-1.335-5.46-5.925 0-1.305.465-2.385 1.23-3.225-.12-.3-.54-1.53.12-3.18 0 0 1.005-.315 3.3 1.23.96-.27 1.98-.405 3-.405s2.04.135 3 .405c2.295-1.56 3.3-1.23 3.3-1.23.66 1.65.24 2.88.12 3.18.765.84 1.23 1.905 1.23 3.225 0 4.605-2.805 5.625-5.475 5.925.435.375.81 1.095.81 2.22 0 1.605-.015 2.895-.015 3.3 0 .315.225.69.825.57A12.02 12.02 0 0024 12c0-6.63-5.37-12-12-12z" /></svg> GitHub</label><label for="none-alphamissense-db" class="tool-tab tab-close badge-github"><svg width="14" height="14" viewBox="0 0 24 24" fill="currentColor"><path d="M12 0C5.37 0 0 5.37 0 12c0 5.31 3.435 9.795 8.205 11.385.6.105.825-.255.825-.57 0-.285-.015-1.23-.015-2.235-3.015.555-3.795-.735-4.035-1.41-.135-.345-.72-1.41-1.23-1.695-.42-.225-1.02-.78-.015-.795.945-.015 1.62.87 1.845 1.23 1.08 1.815 2.805 1.305 3.495.99.105-.78.42-1.305.765-1.605-2.67-.3-5.46-1.335-5.46-5.925 0-1.305.465-2.385 1.23-3.225-.12-.3-.54-1.53.12-3.18 0 0 1.005-.315 3.3 1.23.96-.27 1.98-.405 3-.405s2.04.135 3 .405c2.295-1.56 3.3-1.23 3.3-1.23.66 1.65.24 2.88.12 3.18.765.84 1.23 1.905 1.23 3.225 0 4.605-2.805 5.625-5.475 5.925.435.375.81 1.095.81 2.22 0 1.605-.015 2.895-.015 3.3 0 .315.225.69.825.57A12.02 12.02 0 0024 12c0-6.63-5.37-12-12-12z" /></svg> GitHub</label></span> <span class="tool-tab-wrap"><label for="paper-alphamissense-db" class="tool-tab tab-open badge-paper"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M14 2H6a2 2 0 0 0-2 2v16a2 2 0 0 0 2 2h12a2 2 0 0 0 2-2V8z" /><polyline points="14 2 14 8 20 8" /><line x1="16" y1="13" x2="8" y2="13" /><line x1="16" y1="17" x2="8" y2="17" /><polyline points="10 9 9 9 8 9" /></svg> Publication</label><label for="none-alphamissense-db" class="tool-tab tab-close badge-paper"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M14 2H6a2 2 0 0 0-2 2v16a2 2 0 0 0 2 2h12a2 2 0 0 0 2-2V8z" /><polyline points="14 2 14 8 20 8" /><line x1="16" y1="13" x2="8" y2="13" /><line x1="16" y1="17" x2="8" y2="17" /><polyline points="10 9 9 9 8 9" /></svg> Publication</label></span> <span class="tool-tab-wrap"><label for="cite-alphamissense-db" class="tool-tab tab-open badge-cite"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M3 21c3 0 7-1 7-8V5c0-1.25-.756-2.017-2-2H4c-1.25 0-2 .75-2 1.972V11c0 1.25.75 2 2 2 1 0 1 0 1 1v1c0 1-1 2-2 2s-1 .008-1 1.031V20c0 1 0 1 1 1z" /><path d="M15 21c3 0 7-1 7-8V5c0-1.25-.757-2.017-2-2h-4c-1.25 0-2 .75-2 1.972V11c0 1.25.75 2 2 2h.75c0 2.25.25 4-2.75 4v3c0 1 0 1 1 1z" /></svg> Cite</label><label for="none-alphamissense-db" class="tool-tab tab-close badge-cite"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M3 21c3 0 7-1 7-8V5c0-1.25-.756-2.017-2-2H4c-1.25 0-2 .75-2 1.972V11c0 1.25.75 2 2 2 1 0 1 0 1 1v1c0 1-1 2-2 2s-1 .008-1 1.031V20c0 1 0 1 1 1z" /><path d="M15 21c3 0 7-1 7-8V5c0-1.25-.757-2.017-2-2h-4c-1.25 0-2 .75-2 1.972V11c0 1.25.75 2 2 2h.75c0 2.25.25 4-2.75 4v3c0 1 0 1 1 1z" /></svg> Cite</label></span> <span class="tool-tab-wrap"><label for="source-alphamissense-db" class="tool-tab tab-open badge-source"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><polyline points="16 18 22 12 16 6" /><polyline points="8 6 2 12 8 18" /></svg> Tool Source</label><label for="none-alphamissense-db" class="tool-tab tab-close badge-source"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><polyline points="16 18 22 12 16 6" /><polyline points="8 6 2 12 8 18" /></svg> Tool Source</label></span> <span class="tool-tab-wrap"><label for="notebook-alphamissense-db" class="tool-tab tab-open badge-notebook"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M2 3h6a4 4 0 0 1 4 4v14a3 3 0 0 0-3-3H2z" /><path d="M22 3h-6a4 4 0 0 0-4 4v14a3 3 0 0 1 3-3h7z" /></svg> Open as Notebook</label><label for="none-alphamissense-db" class="tool-tab tab-close badge-notebook"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M2 3h6a4 4 0 0 1 4 4v14a3 3 0 0 0-3-3H2z" /><path d="M22 3h-6a4 4 0 0 0-4 4v14a3 3 0 0 1 3-3h7z" /></svg> Open as Notebook</label></span> <span class="tool-tab-wrap"><label for="proto-alphamissense-db" class="tool-tab tab-open badge-proto"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M13 2L3 14h9l-1 8 10-12h-9l1-8z" /></svg> Open on Proto</label><label for="none-alphamissense-db" class="tool-tab tab-close badge-proto"><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M13 2L3 14h9l-1 8 10-12h-9l1-8z" /></svg> Open on Proto</label></span>
</div>

<a href="https://github.com/google-deepmind/alphamissense" target="_blank" class="tab-panel github-panel" data-tab="github-alphamissense-db">
  <div class="gh-card-wrap">
    <img src="https://opengraph.githubassets.com/1/google-deepmind/alphamissense" class="gh-card-img img-fallback" alt="google-deepmind/alphamissense" />

    <div class="gh-card-fallback">
      <div class="gh-fallback-org"><svg width="14" height="14" viewBox="0 0 24 24" fill="currentColor"><path d="M12 0C5.37 0 0 5.37 0 12c0 5.31 3.435 9.795 8.205 11.385.6.105.825-.255.825-.57 0-.285-.015-1.23-.015-2.235-3.015.555-3.795-.735-4.035-1.41-.135-.345-.72-1.41-1.23-1.695-.42-.225-1.02-.78-.015-.795.945-.015 1.62.87 1.845 1.23 1.08 1.815 2.805 1.305 3.495.99.105-.78.42-1.305.765-1.605-2.67-.3-5.46-1.335-5.46-5.925 0-1.305.465-2.385 1.23-3.225-.12-.3-.54-1.53.12-3.18 0 0 1.005-.315 3.3 1.23.96-.27 1.98-.405 3-.405s2.04.135 3 .405c2.295-1.56 3.3-1.23 3.3-1.23.66 1.65.24 2.88.12 3.18.765.84 1.23 1.905 1.23 3.225 0 4.605-2.805 5.625-5.475 5.925.435.375.81 1.095.81 2.22 0 1.605-.015 2.895-.015 3.3 0 .315.225.69.825.57A12.02 12.02 0 0024 12c0-6.63-5.37-12-12-12z" /></svg> google-deepmind/alphamissense</div>
    </div>
  </div>

  <span class="panel-goto-btn gh-goto-btn"><span><svg width="14" height="14" viewBox="0 0 24 24" fill="currentColor"><path d="M12 0C5.37 0 0 5.37 0 12c0 5.31 3.435 9.795 8.205 11.385.6.105.825-.255.825-.57 0-.285-.015-1.23-.015-2.235-3.015.555-3.795-.735-4.035-1.41-.135-.345-.72-1.41-1.23-1.695-.42-.225-1.02-.78-.015-.795.945-.015 1.62.87 1.845 1.23 1.08 1.815 2.805 1.305 3.495.99.105-.78.42-1.305.765-1.605-2.67-.3-5.46-1.335-5.46-5.925 0-1.305.465-2.385 1.23-3.225-.12-.3-.54-1.53.12-3.18 0 0 1.005-.315 3.3 1.23.96-.27 1.98-.405 3-.405s2.04.135 3 .405c2.295-1.56 3.3-1.23 3.3-1.23.66 1.65.24 2.88.12 3.18.765.84 1.23 1.905 1.23 3.225 0 4.605-2.805 5.625-5.475 5.925.435.375.81 1.095.81 2.22 0 1.605-.015 2.895-.015 3.3 0 .315.225.69.825.57A12.02 12.02 0 0024 12c0-6.63-5.37-12-12-12z" /></svg> View repo</span></span>
</a>

<a href="https://doi.org/10.1126/science.adg7492" target="_blank" class="tab-panel paper-panel" data-tab="paper-alphamissense-db">
  <div class="paper-info">
    <div class="paper-title">Accurate proteome-wide missense variant effect prediction with AlphaMissense</div>
    <div class="paper-meta">Jun Cheng, Guido Novati, ... \vZiga Avsec</div>
    <div class="paper-meta paper-venue">Science (2023)</div>
  </div>

  <span class="panel-goto-btn pub-goto-btn"><span><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M14 2H6a2 2 0 0 0-2 2v16a2 2 0 0 0 2 2h12a2 2 0 0 0 2-2V8z" /><polyline points="14 2 14 8 20 8" /><line x1="16" y1="13" x2="8" y2="13" /><line x1="16" y1="17" x2="8" y2="17" /><polyline points="10 9 9 9 8 9" /></svg> Read paper</span></span>
</a>

<div class="tab-panel cite-panel" data-tab="cite-alphamissense-db">
  <div class="cite-code-wrap">
    ```bibtex theme={null}
    @article{cheng2023alphamissense,
      title={Accurate proteome-wide missense variant effect prediction with {AlphaMissense}},
      author={Cheng, Jun and Novati, Guido and Pan, Joshua and Bycroft, Clare and {\v{Z}}emgulyt{\.{e}}, Akvil{\.{e}} and Applebaum, Taylor and Pritzel, Alexander and Wong, Lai Hong and Zielinski, Michal and Sargeant, Tobias and Schneider, Rosalia G. and Senior, Andrew W. and Jumper, John and Hassabis, Demis and Kohli, Pushmeet and Avsec, {\v{Z}}iga},
      journal={Science},
      volume={381},
      number={6664},
      pages={eadg7492},
      year={2023},
      publisher={American Association for the Advancement of Science},
      doi={10.1126/science.adg7492}
    }
    ```
  </div>

  <span class="panel-goto-btn cite-copy-btn"><span><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M3 21c3 0 7-1 7-8V5c0-1.25-.756-2.017-2-2H4c-1.25 0-2 .75-2 1.972V11c0 1.25.75 2 2 2 1 0 1 0 1 1v1c0 1-1 2-2 2s-1 .008-1 1.031V20c0 1 0 1 1 1z" /><path d="M15 21c3 0 7-1 7-8V5c0-1.25-.757-2.017-2-2h-4c-1.25 0-2 .75-2 1.972V11c0 1.25.75 2 2 2h.75c0 2.25.25 4-2.75 4v3c0 1 0 1 1 1z" /></svg> Copy citation</span></span>
</div>

<a href="https://github.com/evo-design/proto-tools/tree/47e34afa5ea240a3b406e323dc38aa5dc85f223e/proto_tools/tools/database_retrieval/alphamissense_db" target="_blank" class="tab-panel source-panel" data-tab="source-alphamissense-db">
  <div class="source-info">
    <img src="https://github.com/evo-design.png?size=40" class="source-avatar" width="36" height="36" />

    <span class="source-path">evo-design/proto-tools<span class="source-subpath">/proto\_tools/tools/database\_retrieval/alphamissense\_db</span></span>
  </div>

  <span class="panel-goto-btn source-goto-btn"><span><svg width="14" height="14" viewBox="0 0 24 24" fill="currentColor"><path d="M12 0C5.37 0 0 5.37 0 12c0 5.31 3.435 9.795 8.205 11.385.6.105.825-.255.825-.57 0-.285-.015-1.23-.015-2.235-3.015.555-3.795-.735-4.035-1.41-.135-.345-.72-1.41-1.23-1.695-.42-.225-1.02-.78-.015-.795.945-.015 1.62.87 1.845 1.23 1.08 1.815 2.805 1.305 3.495.99.105-.78.42-1.305.765-1.605-2.67-.3-5.46-1.335-5.46-5.925 0-1.305.465-2.385 1.23-3.225-.12-.3-.54-1.53.12-3.18 0 0 1.005-.315 3.3 1.23.96-.27 1.98-.405 3-.405s2.04.135 3 .405c2.295-1.56 3.3-1.23 3.3-1.23.66 1.65.24 2.88.12 3.18.765.84 1.23 1.905 1.23 3.225 0 4.605-2.805 5.625-5.475 5.925.435.375.81 1.095.81 2.22 0 1.605-.015 2.895-.015 3.3 0 .315.225.69.825.57A12.02 12.02 0 0024 12c0-6.63-5.37-12-12-12z" /></svg> View source</span></span>
</a>

<a href="https://github.com/evo-design/proto-tools/blob/47e34afa5ea240a3b406e323dc38aa5dc85f223e/proto_tools/tools/database_retrieval/alphamissense_db/examples/example.ipynb" target="_blank" class="tab-panel notebook-panel" data-tab="notebook-alphamissense-db">
  <div class="notebook-info">
    <span class="notebook-icon">
      <svg width="40" height="40" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="1.5" stroke-linecap="round" stroke-linejoin="round">
        <path d="M2 3h6a4 4 0 0 1 4 4v14a3 3 0 0 0-3-3H2z" />

        <path d="M22 3h-6a4 4 0 0 0-4 4v14a3 3 0 0 1 3-3h7z" />
      </svg>
    </span>

    <span class="notebook-label">Open Notebook</span>
  </div>

  <span class="panel-goto-btn notebook-goto-btn"><span><svg width="14" height="14" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M2 3h6a4 4 0 0 1 4 4v14a3 3 0 0 0-3-3H2z" /><path d="M22 3h-6a4 4 0 0 0-4 4v14a3 3 0 0 1 3-3h7z" /></svg> Open notebook</span></span>
</a>

<div class="tab-panel proto-panel" data-tab="proto-alphamissense-db">
  <div class="proto-info">
    <div class="proto-cloud">
      <svg class="proto-cloud-bg" viewBox="0 0 640 512" xmlns="http://www.w3.org/2000/svg">
        <path d="M0 336c0 79.5 64.5 144 144 144H512c70.7 0 128-57.3 128-128c0-61.9-44-113.6-102.4-125.4c4.1-10.7 6.4-22.4 6.4-34.6c0-53-43-96-96-96c-19.7 0-38.1 6-53.3 16.2C367 64.2 315.3 32 256 32C167.6 32 96 103.6 96 192c0 2.7 .1 5.4 .2 8.1C40.2 219.8 0 273.2 0 336z" />
      </svg>

      <img noZoom src="https://mintcdn.com/bio-pro/KVh0EKV-IKblvXR8/assets/logo/evo-logo-light.svg?fit=max&auto=format&n=KVh0EKV-IKblvXR8&q=85&s=0cb66034ba45618505501aee6ea5f5c1" class="proto-panel-logo block dark:hidden" alt="Proto" width="198" height="151" data-path="assets/logo/evo-logo-light.svg" />

      <img noZoom src="https://mintcdn.com/bio-pro/KVh0EKV-IKblvXR8/assets/logo/evo-logo-dark.svg?fit=max&auto=format&n=KVh0EKV-IKblvXR8&q=85&s=2c9e23a14635e60384a434e220788f54" class="proto-panel-logo hidden dark:block" alt="Proto" width="198" height="151" data-path="assets/logo/evo-logo-dark.svg" />
    </div>
  </div>

  <div class="proto-actions">
    <a href="https://proto.evodesign.org/tools/alphamissense-db-fetch" target="_blank" class="proto-action-btn"><span>AlphaMissense Fetch</span><svg width="13" height="13" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><line x1="7" y1="17" x2="17" y2="7" /><polyline points="7 7 17 7 17 17" /></svg></a>
  </div>
</div>

<div class="entity-contributors"><span class="entity-contributors-label">Toolkit contributors</span><span class="entity-contributors-people"><a class="entity-contributor" href="https://github.com/bviggiano" target="_blank" rel="noopener" title="bviggiano: 6 commits"><img noZoom class="entity-contributor-avatar" src="https://avatars.githubusercontent.com/u/21143637?v=4&s=64" alt="" loading="lazy" /><span class="entity-contributor-login">bviggiano</span></a><a class="entity-contributor" href="https://github.com/dguo8412" target="_blank" rel="noopener" title="dguo8412: 2 commits"><img noZoom class="entity-contributor-avatar" src="https://avatars.githubusercontent.com/u/46211285?v=4&s=64" alt="" loading="lazy" /><span class="entity-contributor-login">dguo8412</span></a></span></div>

| Function                       | Description                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| ------------------------------ | ---------------------------------------------------------------------------------------------------- | --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |
| `run_alphamissense_db_fetch()` | Fetch per-residue, per-substitution AlphaMissense pathogenicity scores for a human UniProt access... | <a href="#api-run-alphamissense-db-fetch" class="func-table-btn func-api-btn"><svg width="12" height="12" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><path d="M4 19.5v-15A2.5 2.5 0 0 1 6.5 2H19a1 1 0 0 1 1 1v18a1 1 0 0 1-1 1H6.5a1 1 0 0 1 0-5H20" /></svg> Docs</a> <a href="https://github.com/evo-design/proto-tools/blob/47e34afa5ea240a3b406e323dc38aa5dc85f223e/proto_tools/tools/database_retrieval/alphamissense_db/alphamissense_db_fetch.py#L223" target="_blank" class="func-table-btn func-source-btn"><svg width="12" height="12" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><polyline points="16 18 22 12 16 6" /><polyline points="8 6 2 12 8 18" /></svg> Source</a> |

## Background

AlphaMissense ([Cheng et al., 2023](https://doi.org/10.1126/science.adg7492)) is a deep-learning model that scores the pathogenicity of human missense variants. It is adapted from AlphaFold and fine-tuned on human and primate population variant frequencies, treating variants common in healthy populations as benign and rare variants as putatively pathogenic. For each canonical UniProt sequence it scores all 19 alternate amino acids at every position, covering every possible single missense substitution. Its classification thresholds are set to a cutoff that reaches about 90% precision on ClinVar variants. The paper reports that the model classifies 89% of all 71 million possible human missense variants, labeling 32% likely pathogenic and 57% likely benign at the default thresholds.

The predictions are not computed at query time. They are precomputed by [Google DeepMind](https://deepmind.google/) and distributed as static CSV files by the [AlphaFold Protein Structure Database](https://alphafold.ebi.ac.uk/), maintained by [EMBL-EBI](https://www.ebi.ac.uk/), keyed by UniProt accession at `https://alphafold.ebi.ac.uk/files/AF-{accession}-F1-{suffix}.csv`.

Internally, the tool strips and uppercases the supplied accession, builds the AlphaFold DB CSV URL for the requested coordinate system, and issues a single HTTP GET. The `uniprot` coordinate system fetches the `aa-substitutions` CSV, which holds the full protein-coordinate grid of every possible substitution. The `hg19` and `hg38` coordinate systems fetch the genomic CSVs, which cover only substitutions reachable by a single-nucleotide change (a single-nucleotide variant, SNV) and additionally carry chromosome, position, reference allele, alternate allele, and GENCODE transcript identifier. Each CSV row is parsed into one prediction record, with the genomic fields populated only in genomic mode. A 404 response means the accession is not covered and surfaces as a clear error. Predictions reflect the fixed CSV snapshot published by AlphaFold DB rather than a value recomputed per request.

### Learning Resources

* [AlphaFold DB FAQ](https://alphafold.ebi.ac.uk/faq) (EMBL-EBI) - official documentation covering the AlphaMissense CSV files, coverage, and the genomic and protein coordinate variants.
* [AlphaMissense GitHub](https://github.com/google-deepmind/alphamissense) (Google DeepMind) - the official repository with usage notes for the released code and prediction tables.

## Tools

<a name="api-run-alphamissense-db-fetch" />

<div class="tool-section-card tool-section-card--fetch">
  ### AlphaMissense DB Fetch (`alphamissense-db-fetch`)

  Retrieves the complete AlphaMissense prediction set for a single human UniProt accession and returns every per-substitution prediction, the prediction count, the mean pathogenicity score, and the source CSV URL. The `coordinate_system` configuration selects the protein-coordinate grid of every possible substitution or one of the genomic-coordinate tables, which are limited to substitutions reachable by a single-nucleotide change. The genomic tables additionally populate chromosome, position, reference allele, alternate allele, and transcript identifier on each prediction.

  #### API Reference

  <div class="api-model-section api-input-section">
    <a href="https://github.com/evo-design/proto-tools/blob/47e34afa5ea240a3b406e323dc38aa5dc85f223e/proto_tools/tools/database_retrieval/alphamissense_db/alphamissense_db_fetch.py#L104" target="_blank" class="func-table-btn func-source-btn api-model-source"><svg width="12" height="12" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><polyline points="16 18 22 12 16 6" /><polyline points="8 6 2 12 8 18" /></svg> Source</a>

    <Accordion title="Input: AlphaMissenseDBFetchInput">
      <ParamField path="uniprot_id" type="string" required>
        UniProt accession (must be a human protein covered by AlphaMissense; e.g. 'P04637').
      </ParamField>
    </Accordion>
  </div>

  <div class="api-model-section api-config-section">
    <a href="https://github.com/evo-design/proto-tools/blob/47e34afa5ea240a3b406e323dc38aa5dc85f223e/proto_tools/tools/database_retrieval/alphamissense_db/alphamissense_db_fetch.py#L117" target="_blank" class="func-table-btn func-source-btn api-model-source"><svg width="12" height="12" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><polyline points="16 18 22 12 16 6" /><polyline points="8 6 2 12 8 18" /></svg> Source</a>

    <Accordion title="Config: AlphaMissenseDBFetchConfig">
      <ParamField path="coordinate_system" type="enum" default="uniprot">
        Which AFDB CSV to fetch. `"uniprot"` (default) returns the full protein-coordinate saturation grid (\~7,500 rows for TP53). `"hg19"` / `"hg38"` return SNV-accessible substitutions in genomic coordinates (\~2,500 rows for TP53) and populate `chrom` / `pos` / `ref` / `alt` / `transcript_id` on each prediction; a protein variant reachable by multiple SNVs appears multiple times.

        Available options: `uniprot`, `hg19`, `hg38`
      </ParamField>

      <ParamField path="verbose" type="integer" default="0">
        Verbosity level (0=quiet, 1=info, 2=debug, 3=raw subprocess stderr). `True` is coerced to `1` and `False` to `0`.
      </ParamField>

      <ParamField path="device" type="string" default="cpu">
        Device to run the tool on.
      </ParamField>

      <ParamField path="timeout" type="integer" default="3600">
        Maximum execution time in seconds. `None` waits indefinitely.
      </ParamField>

      <ParamField path="seed" type="integer">
        Random seed. When set, tools run reproducibly up to small GPU float noise (see `BaseToolOutput.approx_equal`), and the seed participates in cache keys. When None, cacheable seed-sensitive tools skip cache until seeded.
      </ParamField>
    </Accordion>
  </div>

  <div class="api-model-section api-output-section">
    <a href="https://github.com/evo-design/proto-tools/blob/47e34afa5ea240a3b406e323dc38aa5dc85f223e/proto_tools/tools/database_retrieval/alphamissense_db/alphamissense_db_fetch.py#L140" target="_blank" class="func-table-btn func-source-btn api-model-source"><svg width="12" height="12" viewBox="0 0 24 24" fill="none" stroke="currentColor" stroke-width="2" stroke-linecap="round" stroke-linejoin="round"><polyline points="16 18 22 12 16 6" /><polyline points="8 6 2 12 8 18" /></svg> Source</a>

    <Accordion title="Output: AlphaMissenseDBFetchOutput">
      <ResponseField name="uniprot_accession" type="string" required>
        UniProt accession that was looked up.
      </ResponseField>

      <ResponseField name="predictions" type="List[AlphaMissensePrediction]">
        All per-substitution pathogenicity predictions in the source CSV (full saturation grid: `sequence_length * 19` for UniProt-coordinate fetches).

        <Expandable title="AlphaMissensePrediction">
          <ResponseField name="position" type="integer" required>
            1-indexed residue position in the canonical UniProt sequence.
          </ResponseField>

          <ResponseField name="wild_type_aa" type="string" required>
            Single-letter wild-type amino acid at this position.
          </ResponseField>

          <ResponseField name="alt_aa" type="string" required>
            Single-letter alternate amino acid being scored.
          </ResponseField>

          <ResponseField name="pathogenicity_score" type="number" required>
            AlphaMissense pathogenicity score (0.0-1.0). Higher values indicate the variant is more likely to be pathogenic.
          </ResponseField>

          <ResponseField name="classification" type="enum" required>
            AlphaMissense class label ('likely\_benign', 'ambiguous', or 'likely\_pathogenic').
          </ResponseField>

          <ResponseField name="chrom" type="string">
            Chromosome (e.g. 'chr17'); populated only for genomic-coordinate fetches.
          </ResponseField>

          <ResponseField name="pos" type="integer">
            1-indexed genomic position; populated only for genomic-coordinate fetches.
          </ResponseField>

          <ResponseField name="ref" type="string">
            Reference allele; populated only for genomic- coordinate fetches.
          </ResponseField>

          <ResponseField name="alt" type="string">
            Alternate allele; populated only for genomic- coordinate fetches.
          </ResponseField>

          <ResponseField name="transcript_id" type="string">
            GENCODE transcript identifier; populated only for genomic-coordinate fetches.
          </ResponseField>
        </Expandable>
      </ResponseField>

      <ResponseField name="num_predictions" type="integer" required>
        Number of predictions in the source CSV.
      </ResponseField>

      <ResponseField name="mean_pathogenicity" type="number">
        Mean pathogenicity score across all predictions; None when `predictions` is empty.
      </ResponseField>

      <ResponseField name="source_url" type="string" required>
        URL of the AlphaMissense CSV that was fetched.
      </ResponseField>
    </Accordion>
  </div>

  #### Applications

  Use this to pull model-based missense pathogenicity into a pipeline: triage missense variants of uncertain significance from clinical sequencing, prioritize candidate disease-causing variants from case cohorts, avoid disruptive substitutions during sequence design or optimization, or apply a per-residue pathogenicity penalty in a generative-design loop. The accession can come from the [UniProt](https://bio-pro.mintlify.app/tools/database-retrieval/uniprot) tool, which resolves a gene symbol and organism to a canonical reviewed human accession. The same accession also drives the [AlphaFold DB](https://bio-pro.mintlify.app/tools/database-retrieval/alphafold-db) tool, aligning per-residue pathogenicity scores with predicted backbone coordinates.

  #### Usage Tips

  * **The tool always returns the entire prediction set.** There is no server-side filtering on the static CSV. Filter the returned `predictions` list in your own code by position, score, or classification.
  * **Cache the output once per accession.** A typical protein has roughly 7,000 to 20,000 substitution rows. Fetch once and reuse the result rather than refetching inside tight loops.
  * **Group by `position` for hotspot analysis.** `mean_pathogenicity` over a wide region is a coarse summary. Inspect predictions grouped by residue position to surface hotspots.
  * **Coverage is human canonical isoforms only.** Non-canonical isoforms and non-human accessions return a 404 and surface as a clear error. Resolve the accession with the UniProt tool first if the organism is uncertain.
</div>

## Toolkit Notes

These apply to every AlphaMissense DB tool in this toolkit (`alphamissense-db-fetch`).

* **Requires network access.** The tool downloads the AlphaMissense CSV from the AlphaFold Protein Structure Database. It does not run offline and keeps no local copy of the predictions.
* **Subject to EMBL-EBI fair use.** The CSV is an anonymous static download from AlphaFold DB with no API key or account. Observe the [EMBL-EBI terms of use](https://www.ebi.ac.uk/about/terms-of-use/) and space out high-volume requests.

<Tip>
  **Example notebook:** See the [full working example](https://github.com/evo-design/proto-tools/blob/47e34afa5ea240a3b406e323dc38aa5dc85f223e/proto_tools/tools/database_retrieval/alphamissense_db/examples/example.ipynb) for a copy-paste-ready walkthrough.
</Tip>

## Infrastructure Guides

The following guides cover how to run tools efficiently and at scale.

<CardGroup cols={2}>
  <Card title="Tool Persistence" icon="repeat" href="/docs/tools/guides/tool-persistence">Keep a tool's model warm across calls instead of reloading it every invocation.</Card>
  <Card title="Device Management" icon="cpu" href="/docs/tools/guides/device-management">How GPUs are allocated to tools and how to target specific devices.</Card>
  <Card title="Parallel Execution" icon="layers" href="/docs/tools/guides/parallel-execution">Fan a batch of inputs out across multiple GPUs.</Card>
</CardGroup>
