Risk Beyond the Variant: A Composite Metric for Autism Gene Pathogenicity

Variant-based pathogenicity predictors such as REVEL evaluate missense variants in isolation, discarding the gene-length and allele-frequency context needed to compare collections of genes. In this paper, we introduce a composite gene-level metric integrating Hardy-Weinberg heterozygosity, coding-sequence length, and REVEL scores, evaluated on 55 high-confidence autism genes against the 1000 Genomes reference. It identifies elevated pathogenic burden in 48 of 55 genes, removes gene-length and variant-count confounds, and outperforms REVEL-only scoring by a large margin. Bootstrap resampling and a label-permutation control confirm the enrichment is stable and not an artefact of the scoring construction. We present it as a complementary gene-level layer for case-control and gene-set comparisons, with a nonlinear successor outlined as future work.