doi.org
Phenotypes of ultra-rare variant carriers benchmark variant effect scores
Human genetics needs benchmarks for evaluating variant scores against observed phenotypic consequences. We therefore present UKBBGym, which evaluates coding and non-coding scores against plasma protein abundance and quantitative traits observed in carriers of ultra-rare variants in the UK Biobank. This design avoids ascertainment biases of clinical labels, potential physiological mismatch of experimental assays, and confounding pertaining to common-variant associations. UKBBGym recapitulates relative performance on pathogenicity prediction while enabling comparison across variant classes and molecular mechanisms. This shows that scores designed for coding and splicing variants correlate more strongly with protein abundance and quantitative traits than scores modelling transcriptional regulation. Moreover, experimental assays do not consistently outperform computational scores for predicting missense effects. Comparing captured to detectable variance indicates scope for improvement, particularly for indels and loss-of-function variants. Finally, for coding variants, UKBBGym can be reproduced from public summary statistics, providing an accessible population-phenotype benchmark complementary to clinical labels and experimental assays. ### Competing Interest Statement The authors have declared no competing interest. Helmholtz Association of German Research Centres, project DeepVar, ZT-I-PF-5-156 Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, 535971044, 461264291, 553375143 European Research Council, 101118521 European Molecular Biology Organization, Scientific Exchange Grant #12502 European Union, Horizon Europe research and innovation program under grant agreement N°101156595
