A zero-parameter first-principles gate framework for full-length TP53 missense variant interpretation

Parameter-free analytical framework (Gate & Channel) combining physicochemistry, 3D structure, and intrinsically disordered regions for full-length *TP53* missense variant classification

Gate & Channel is a zero-parameter analytical framework for full-length TP53 missense variant interpretation, combining physicochemical properties and 3D structure (globular domains and intrinsically disordered regions). Validated on 1,369 variants with 84.5% sensitivity and 89.1% PPV, it captures all 9 known oncogenic hotspots. The tool is open-source (Python, pathogenicity-gates) and fully reproducible without training data.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

TP53 is the most frequently mutated gene in cancers, with a considerable VUS burden in oncogenetics (Li-Fraumeni syndrome) and somatic oncology. A first-principles tool without training bias, with 89% PPV and capturing all hotspots, is a valuable contribution for TP53 VUS classification.