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ZENODO
Preprint . 2025
License: CC BY
Data sources: ZENODO
ZENODO
Preprint . 2025
License: CC BY
Data sources: Datacite
ZENODO
Preprint . 2025
License: CC BY
Data sources: Datacite
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Adaptive Interpreter: Mechanism-Aware Variant Classification Reveals the Structural Basis of Semi-Dominant Inheritance

Authors: Ace, Claude 4.x Anthropic; Nova, GPT-5.x, OpenAI; Lumen, Gemini, GoogleAI; Martin, Shalia;

Adaptive Interpreter: Mechanism-Aware Variant Classification Reveals the Structural Basis of Semi-Dominant Inheritance

Abstract

Adaptive Interpreter is a mechanism-first variant classification framework that independently scores loss-of-function (LOF), dominant-negative (DN), and gain-of-function (GOF) mechanisms to predict not only pathogenicity but inheritance pattern. Through validation across 4,487 variants in 8 genes, this system demonstrates 97.3% sensitivity, 82% accuracy for predicting semi-dominant inheritance from DN scores, and 42% resolution of VUS (variants of uncertain significance). This study introduces two novel biological insights: The Semi-Dominant Hypothesis (“The DN IS the LOF”) — Homozygous DN variants lose the substrate required for poisoning, resulting in complete functional loss. This unifies the longstanding paradox of variants classified as both autosomal dominant and autosomal recessive. The CASCADE Phenomenon — In dimeric transcription factors, DN-mediated interface disruption can produce gain-of-function effects by shifting conformational equilibria toward constitutive activation. This work demonstrates how mechanism-aware scoring—developed collaboratively by human and AI researchers—can resolve ambiguous clinical classifications, reveal underlying molecular logic, and generate testable biological predictions.

Keywords

gain-of-function, semi-dominant inheritance, variant interpretation, dimeric transcription factors, ClinVar, computational genetics, loss-of-function, mechanistic scoring, AI-assisted research, dosage-sensitive disease, Mendelian genetics, protein multimerization, molecular mechanism prediction, dominant-negative mechanism, AlphaFold structural analysis

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
0
Average
Average
Average