finding

active

finding:mechanistic-explanations-provided-for-2m-variants-of-uncertain-significance

Mechanistic explanations provided for ~2M variants of uncertain significance

Scale of interpretability output, addressing a major clinical need for VUS resolution.

Source paper

extracted_from

Explaining 4.2 million genetic variants with state-of-the-art, interpretable predictions

(2026) · Pearce, Michael · Dooms, Thomas · Yamamoto, Ryo · Meehl, Joshua +18

Neighborhood — ranked by edge-count

Papers (1)

paper

Explaining 4.2 million genetic variants with state-of-the-art, interpretable predictions
mentions

Claims (2)

claim

Evee provides predictions and mechanistic explanations for 4.2 million genetic variants across the whole human genome
supports
Scale claim, demonstrating whole-genome applicability.
Interpretable predictions can help resolve variants of uncertain significance
supports
Motivating claim that mechanistic explanations add clinical value for VUS.

Communities (2)

community

Mechanistic interpretability & model evaluation
members_of
Spans attention head decomposition, benchmark awareness, and genomic pathogenicity prediction via neural models.
Mechanistic explanation of genetic variant pathogenicity
members_of
Using genomic foundation model internals to generate disruption profiles that explain variant effects mechanistically, achieving 0.997 AUROC on ClinVar pathogenicity prediction.

Related by similarity (8)

cosine ≥ 0.65 · no typed edge

Entities in the same semantic neighborhood but without a typed relation to this one — candidates for new edges or unrecognized duplicates.

variant of uncertain significance (VUS)concept0.739
Genetic variants whose clinical impact is unknown; a key motivation for the work, ~2M of which are explained.
Table 1: Sources of Uncertainty Scored by Expected Free Energy and the Behaviors Entailedconcept0.729
Summary table mapping uncertainty types to free energy formulations and corresponding behaviors
Under spatio permutation controls, IIT consciousness estimates outperform Span Representation in mean AUC in several cases (LLaMA3.1-70B on Hinting and Irony, Mistral-7B on Irony, LLaMA3.1-8B on Strange Stories).finding0.729
Contrasts with temporal permutation where Span Representation dominates; suggests spatio permutation reveals different dynamics.
Model internals of genomic foundation models can yield mechanistic explanations for variant effectsclaim0.729
Foundational interpretability claim that the paper exemplifies.
mechanistic explanationconcept0.722
Explanations derived from model internals that describe the biological mechanism of variant effect.
Variations in ToM test score categories are more likely attributed to span-level information of the LLM representation sequence rather than to a 'consciousness' phenomenon as suggested by IIT estimates.claim0.720
Main interpretive finding from Criterion 3 comparison showing Span Representation consistently outperforms IIT under temporal permutation.
Ambiguous anchors (33-27=60, 11-9=20) yield four distinct arithmetic interpretations across M1-M4finding0.719
Models produce different answers (240, 138, -240) from the same ambiguous prompt
Ambiguous 2-shot anchors yield four distinct interpretations across M1-M4 (P_abs-mult, P_add x2, P_signed-mult)finding0.718
E1 finding showing that near-threshold, marginal model differences tilt to qualitatively different bindings