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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

86%

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SecuritybySnyk

Low

Low-risk findings worth noting

SKILL.md
Quality
Evals
Security

Quality

Content

77%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.

An excellent, highly actionable workflow with concrete tool calls, thresholds, decision tables, validation, and honest limitations. The weaknesses are token efficiency and structure: the optional ThermoMPNN section with its commercial vendor listing is verbose and should live in a separate reference file.

Suggestions

Move the 'Optional: ThermoMPNN' section (local install, SaaS vendor list, license notes) into a references/thermompnn.md file and keep a 2-3 line pointer in SKILL.md stating when the higher-accuracy model matters (near-threshold ddG, double mutants, indels).

Trim the ThermoMPNN 'When it actually matters' section to the three-bullet decision rule; the DynaMut2-vs-ThermoMPNN justification narrative can be cut since DynaMut2 is already the stated default.

Optionally extract the Step 6 mechanism decision table and the reporting template into a reference file so the core SKILL.md stays a lean workflow overview.

DimensionReasoningScore

Conciseness

The workflow core (Steps 0-7) is lean tables and code, but the 'Optional: ThermoMPNN' section (~45 lines) enumerates five commercial SaaS vendors, a conda install walkthrough, and license citations that are tangential to the skill's core use case. Mostly efficient, but noticeably could be tightened, matching anchor 3; it is not anchor 2 because the majority of tokens earn their place.

3 / 5

Actionability

Every step ships executable tool calls with real parameters (e.g. AlphaMissense_get_variant_score(uniprot_id="P04637", position=175, ref_aa="R", alt_aa="H")), a variant-string regex, numeric decision thresholds (>=0.564, pLDDT > 70, dLogP < -1, ddG > +1), and a copy-paste reporting template, all illustrated by a worked example (TP53 R175H).

5 / 5

Workflow Clarity

Steps 0-7 are clearly sequenced with explicit validation checkpoints (assert sequence[position - 1] == ref_aa), early-exit guidance (AlphaMissense benign <=0.34 makes the rest exploratory), fallback branches (no experimental PDB -> use the AlphaFold model), and a final evidence-grading step with conflict handling, matching the anchor-5 feedback-loop pattern.

5 / 5

Progressive Disclosure

Headers are well organized and the skill is self-contained (no bundle files exist to mis-navigate), but everything is inline in a single ~290-line SKILL.md: the ThermoMPNN advanced section and its SaaS vendor list clearly belong in a separate reference file. This fits anchor 3 ('content that should be separate is inline'); not anchor 4 because the optional tangent is substantial.

3 / 5

Total

16

/

20

Passed

Description

87%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 highly specific, complete description that names the five evidence layers, the two mechanism categories it distinguishes, and an explicit use-when clause. The only deductions are second-person phrasing in the trigger clause and a couple of missing natural trigger synonyms.

DimensionReasoningScore

Specificity

The description lists multiple concrete, comprehensive actions ('Propose the mechanism by which a missense variant causes loss-of-function (LoF), synthesizing evidence from 5 independent layers', 'Distinguishes "structural stability LoF" (mis-folding) from "direct functional disruption" (catalytic / binding / PTM site damage)'), which matches the 5 anchor. However, 'Use for coding missense variants where you need a mechanistic causal model' is second-person voice, and the judging guidelines penalize second person by reducing specificity by 1.

4 / 5

Completeness

Clearly answers both: 'what' (propose a mechanism by synthesizing 5 named evidence layers and distinguishing two LoF categories) and an explicit 'when' ('Use for coding missense variants where you need a mechanistic causal model, not just a pathogenicity score'), matching the anchor-5 example structure.

5 / 5

Trigger Term Quality

Good keyword coverage with natural domain terms ('missense variant', 'loss-of-function (LoF)', 'pathogenicity score', 'mechanistic causal model') including the abbreviation expansion, but a few natural user phrasings are missing (e.g. 'why is this variant damaging', 'variant effect'), so it sits between the 4 and 5 anchors, closer to 4.

4 / 5

Distinctiveness Conflict Risk

It carves out a clear niche (missense LoF mechanism synthesis) with named tools and an explicit contrast against mere pathogenicity scoring, so the risk of triggering for a sibling variant-interpretation skill is minimal.

5 / 5

Total

18

/

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

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

Reviewed

Table of Contents

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