ArticlebioRxiv : the preprint server for biology2026
Homology-Based Variant-Effect Predictors Break Down on Cytochrome P450 Pharmacogenes.
Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Cytochrome P450 (CYP) enzymes metabolize roughly three-quarters of clinically used drugs, and genetic variation in these enzymes is a leading source of interindividual differences in drug response. Predicting a variant's functional effect is therefore critical, yet the consequences of most CYP variants remain unknown. Many state-of-the-art variant-effect predictors rest on a homology-based paradigm that scores variants by evolutionary conservation - an assumption that pharmacogenes, including CYPs, violate. Focusing on human CYPs, we show that homology-based models fail systematically. AlphaMissense (AM) assigns variants to its "ambiguous" class at nearly twice the proteome-wide rate across six clinically important CYPs, and within that class its scores are essentially uninformative about measured CYP2C9 deep mutational scan (DMS) activity (
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