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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.

Quality

91%

Does it follow best practices?

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SecuritybySnyk

Low

Low-risk findings worth noting

The canonical home for this skill is tooluniverse-protein-lof-mechanism in mims-harvard/ToolUniverse

SKILL.md
Quality
Evals
Security

Quality

Content

85%Weight 40%Scale 1-5

Reviews the quality of instructions and guidance provided to agents. Good implementation is clear, handles edge cases, and produces reliable results.

The workflow content is excellent: fully executable tool calls with explicit thresholds, validation checkpoints at every step, and an honest limitations section. The main weakness is structure — the whole skill is one long file, and the optional ThermoMPNN material (install instructions, five commercial SaaS vendors, licensing) should be split into a reference file with a pointer from SKILL.md.

Suggestions

Move the 'Optional: ThermoMPNN instead of DynaMut2' section (local install, SaaS vendor list, licensing) into references/thermompnn.md and keep only a 2-3 line pointer in SKILL.md with the decision rule for when it matters (near-threshold ΔΔG, double mutants, indels).

Trim editorial asides in the ThermoMPNN section ('Not as clean as DynaMut2's purely academic endpoint, which is why TU defaults to DynaMut2') to reduce token load without losing the guidance.

The reporting-format template duplicates information also implied by Steps 6-7; consider consolidating the mechanism-category table and the confidence grading into the report template section to avoid two passes over the same decision logic.

DimensionReasoningScore

Conciseness

The body is largely efficient — domain-specific tool calls, threshold tables, and decision rules that Claude does not already know, with no padding explaining basic concepts. However the ~45-line optional ThermoMPNN section (vendor SaaS listings, conda install walkthrough, license notes) and chatty asides like 'Not as clean as DynaMut2's purely academic endpoint, which is why TU defaults to DynaMut2' are trimmable. This matches the score-4 anchor (efficient; minor instances of over-explanation that could be trimmed) rather than 5, since every token does not quite earn its place.

4 / 5

Actionability

Every step has copy-paste-ready tool invocations with exact parameters (e.g. 'ESM_explain_variant_mechanism(sequence=..., position=175, ref_aa="R", alt_aa="H", window=8, top_k_features=5)'), numeric decision thresholds (pLDDT >70, ΔlogP < −1, ddG > +1 kcal/mol), a variant-string parsing regex, and a fill-in reporting template. This matches the score-5 anchor (fully executable, copy-paste ready, covering the common cases).

5 / 5

Workflow Clarity

Steps 0–7 are clearly sequenced with explicit validation checkpoints: the reference-residue assert in Step 0 ('assert sequence[position - 1] == ref_aa'), the benign-score gating in Step 1, the pLDDT reliability gating in Step 2, and the honest evidence-grading and limitations sections in Step 7. This matches the score-5 anchor (clear sequence with explicit validation and feedback on conflicting signals); it is not a destructive/batch operation so no cap applies.

5 / 5

Progressive Disclosure

The skill is a single monolithic ~290-line SKILL.md with no bundle files (no references/, scripts/, or assets/ exist). Section headers are good, but the advanced optional content — the entire ThermoMPNN local-install, SaaS-vendor, and license material — is inlined in the main file rather than split into a one-level-deep reference file. This matches the score-3 anchor (some structure, but content that should be separate is inline); it is above 2 because the in-file organization and navigation are solid, but below 4 because the optional material clearly belongs in its own file.

3 / 5

Total

17

/

20

Passed

Description

92%Weight 40%Scale 1-5

Based on the skill's description, can an agent find and select it at the right time? Clear, specific descriptions lead to better discovery.

A strong description: it states concrete, third-person capabilities with all five evidence layers and two mechanism categories named, and gives an explicit 'Use for...' clause with concrete triggers. The only weakness is slightly thin synonym coverage of natural trigger terms.

Suggestions

Add common synonyms for trigger coverage, e.g. 'Use for missense variants (amino acid substitutions) such as TP53 R175H where you need the loss-of-function mechanism, not just a pathogenicity score.'

DimensionReasoningScore

Specificity

The description lists multiple concrete actions — 'Propose the mechanism by which a missense variant causes loss-of-function (LoF), synthesizing evidence from 5 independent layers' with each layer named (AlphaMissense, AlphaFold, ESMC, SAE, DynaMut2) — plus a concrete distinction between 'structural stability LoF' (mis-folding) and 'direct functional disruption'. It uses third-person voice throughout. This matches the score-5 anchor (multiple specific concrete actions, comprehensive coverage) rather than 4, since there are no minor gaps in coverage of what the skill does.

5 / 5

Completeness

It explicitly answers 'what' ('Propose the mechanism... synthesizing evidence from 5 independent layers... Distinguishes structural stability LoF from direct functional disruption') and 'when' ('Use for coding missense variants where you need a mechanistic causal model, not just a pathogenicity score') with concrete trigger phrasing. This matches the score-5 anchor exactly; the 'when' clause is both explicit and specific, not merely present as at 4.

5 / 5

Trigger Term Quality

Natural domain terms are present — 'missense variant', 'loss-of-function (LoF)', 'pathogenicity score', 'mechanistic causal model' — which a user needing this skill would plausibly say. However it misses common synonyms and variations such as 'amino acid substitution', 'protein variant', or 'missense mutation', so it fits the score-4 anchor (good keyword coverage; a few natural terms missing) rather than 5's comprehensive synonym coverage.

4 / 5

Distinctiveness Conflict Risk

The description carves out a clear niche — mechanistic causal modeling of coding missense variants — and actively distinguishes itself from adjacent capabilities ('not just a pathogenicity score'), minimizing conflict risk with generic variant-interpretation skills. It matches the score-5 anchor (clear niche with distinct triggers, minimal conflict risk).

5 / 5

Total

19

/

20

Passed

Validation

100%

Checks the skill against the spec for correct structure and formatting. All validation checks must pass before discovery and implementation can be scored.

Validation — 16 / 16 Passed

Validation for skill structure

No warnings or errors.

Repository

mims-harvard/ToolUniverse

Path

plugins/tooluniverse/skills/tooluniverse-protein-lof-mechanism/SKILL.md

Reviewed

Table of Contents

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