DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features

Despite an increasing use of genomic sequencing in clinical practice, interpretation of rare genetic variants remains challenging even in well-studied disease genes, resulting in many patients with Variants of Uncertain Significance (VUSs). Computational Variant Effect Predictors (VEPs) are currently used to provide valuable evidence in variant classifications, but they often misclassify benign variants, contributing to potential misdiagnoses. Here, we developed Deciphering Mutations in Actionable Genes (DeMAG), a supervised classifier for interpreting missense variants in actionable disease genes with improved performance over existing VEPs (20% decrease of false positive rate). Our tool has balanced specificity (82%) and sensitivity (94%) on clinical data, and the lowest misclassification rate on putatively benign variants among evaluated tools. DeMAG takes advantage of a novel epistatic feature, the ‘partners score’, which is based on evolutionary and structural partnerships of residues as estimated by evolutionary information and AlphaFold2 structural models. The ‘partners score’ as a general framework of epistatic interactions, can integrate not only clinical but functional information. We anticipate that our tool (demag.org) will facilitate the interpretation of variants and improve clinical decision-making.