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The GA4GH Categorical Variation Representation Specification: A Unified Computational Framework for Reasoning over Genomic Variant Categories

Puthawala, D.; Reardon, B.; Babb, L.; Kuzma, K.; Stevenson, J. S.; Goar, W. A.; Dolin, R. H.; Freimuth, R. R.; Procknow, C.; Pitel, B.; Kundu, P.; Rampersad, A.; Van Allen, E. M.; Wagner, A. H.

2026-02-12 genomics
10.64898/2026.02.10.705161 bioRxiv
Show abstract

Categorical variants, or sets of genomic alterations constrained by shared properties, are pervasive across clinical, regulatory, and research domains in the biomedical ecosystem, yet their inconsistent and non-computable representation hinders data interoperability and clinical interpretation. We surveyed genomic knowledgebases spanning regulatory approvals and the biomedical literature and found that categorical variants underpin a substantial proportion of clinical genomics knowledge, but are largely described using incompatible bespoke models. To address this, we developed the GA4GH Categorical Variation Representation Specification (Cat-VRS), a constraint-based framework that provides a unified computable representation for both precise and intentionally broad categories across molecular and systemic variant domains. Cat-VRS enables harmonization of genomic knowledgebases, computable category-based search, and automated matching between assayed variants and categorical entities in clinical and research contexts. By providing a principled, extensible model for categorical variation, Cat-VRS enables computable reasoning over genomic variant categories and establishes a foundation for the standardized representation and exchange of genomic knowledge.

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