Variant scoring performance across selection regimes depends on variant-to-gene and gene-to-disease components
Open accessAbstract
Variant scoring methods (VSMs) aid in the interpretation of coding mutations and their potential impact on health, but their evaluation in the context of human genetics applications remains inconsistent. Here, we describe GeneticsGym, a systematic approach to evaluating the real-world impact of VSMs on human genetic analysis. We show that the relative performance of VSMs varies across regimes of natural selection, and that both variant-to-gene and gene-to-disease components contribute.
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Application of AlphaGenome to complex trait analysis is limited because it predicts molecular consequences of variants, whereas these phenotypes involve broader biological processes (including gene function, development and environmental factors) and gene-to-disease effects beyond the model's direct sequence-to-function scope.
“Finally, application to complex trait analysis is limited because AlphaGenome predicts molecular consequences of variants, whereas these phenotypes involve broader biological processes (including gene function, development and environmental factors) and gene-to-disease effects42 beyond the direct sequence-to-function scope of the model.”
From Advancing regulatory variant effect prediction with AlphaGenome (2026) · cites this paper as [42]
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References 19 · Cited by 4
- Authors
- Finucane, H. K., Parsa, S., Guez, J., Kanai, M., Satterstrom, F. K., Nkambule, L. L., Daly, M. J., Seed, C., & Karczewski, K. J.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Finucane, Hilary K.
- Karczewski, Konrad J.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2024-09-19
- OpenAlex
- W4402694380
- Cited by
- 4
- References
- 19
- Citations by year
- 2026: 2 · 2025: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- variant effect prediction, natural selection, selection regimes, coding mutations, variant interpretation, benchmarking
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