Phenotypes of ultra-rare variant carriers benchmark variant effect scores
- 1School of Computation, Information and Technology, Technical University of Munich, Garching, Germany
Abstract
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.
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BibTeX
@misc{londhe2026phenotypes,
title = {{Phenotypes of ultra-rare variant carriers benchmark variant effect scores}},
author = {S. Londhe and E. Holtkamp and G. Tsitsiridis and A. Starovoit and P. Tomaz da Silva and J. Hingerl and H. Finucane and J. Gagneur},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755962},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755962v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Phenotypes of ultra-rare variant carriers benchmark variant effect scores
AU - S. Londhe
AU - E. Holtkamp
AU - G. Tsitsiridis
AU - A. Starovoit
AU - P. Tomaz da Silva
AU - J. Hingerl
AU - H. Finucane
AU - J. Gagneur
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755962
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755962v1
AB - 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.
ER -