DPYD Variant Pathogenicity Classifier

Versions

• v1: Baseline — 273 training rows, 4 decreased_function examples, F1=0.0 for decreased_function
• v2: +Offer 2014 + PharmVar data, SMOTE, domain features — 392 rows, 23 decreased_function examples, F1=0.66 (XGB)
• v3: +AlphaMissense + CADD + VEP annotations on training set — AM importance 0→0.01, sentinel gap closed
• v4: protein-only model — drop clnsig_norm/activity_pct/AF, keep AM/CADD/SIFT/PolyPhen/domain/aa_position/vep_consequence. 13/25 Scaria variants changed class (no_function→decreased_function). CV accuracy 0.91→0.73 (expected — label proxy removed). Best model: lgbm (decreased_function F1=0.25).

Two-tier inference note

• The protein-only classifier (v4) is preferred when class discrimination between decreased_function and no_function is required. Unlike v1–v3, v4 does not default novel variants to no_function (it reclassified 13/25 Scaria variants), at the cost of in-distribution accuracy it does not need on this tail.
• The raw AlphaMissense score is sufficient when the clinical question is simply pathogenicity vs. benign.

Ground truth sources

Citation