Individual skill
tooluniverse-protein-lof-mechanism
Propose the mechanism by which a missense variant causes loss-of-function (LoF), synthesizing evidence from 5 independent layers: AlphaMissense pathogenicity, AlphaFold structural context, ESMC sequence likelihood, SAE feature disruption, and DynaMut2 stability ΔΔG. Distinguishes 'structural stability LoF' (mis-folding) from 'direct functional disruption' (catalytic / binding / PTM site damage). Use for coding missense variants where you need a mechanistic causal model, not just a pathogenicity score.
plugins/tooluniverse/skills/tooluniverse-protein-lof-mechanism/SKILL.md
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# Protein LoF Mechanism Synthesis
For a single missense variant, integrate 5 independent computational signals to propose a specific loss-of-function mechanism. Each signal answers a different question:
| Signal | Tool | Answers |
|---|---|---|
| Pathogenicity | `AlphaMissense_get_variant_score` | "Is this variant damaging?" |
| Structural context | `alphafold_get_prediction` | "Is the mutation in a folded vs disordered region?" |
| Sequence likelihood | `ESM_score_sequence` | "Is the substitution evolutionarily plausible?" |
| Feature disruption | `ESM_explain_variant_mechanism` (or `ESM_score_variant_sae_disruption` + `ESM_describe_sae_feature` for raw control) | "Which biological feature breaks?" |
| Stability | `DynaMut2_predict_stability` | "Does the protein still fold correctly?" |
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