Rare coding and noncoding variants map 1,342 diseases and biomarkers in 490,549 whole genomes

Rare genetic variants are increasingly recognized as important contributors to human trait architecture, with noncoding variants accounting for a substantial portion of the heritability. These variants tend to be less polygenic and more biologically specific than common variants, remaining understudied across large biobanks. Here we analyzed whole genome sequencing (WGS) data from up to 490,549 UK Biobank participants to assess the effects of rare coding and noncoding variants across 1,342 phenotypes, including 944 diseases, 76 clinical biomarkers, and 322 metabolomics traits. We developed and applied STAARpipelinePheWAS, a scalable framework for WGS phenome-wide rare variant association analysis, identifying 49,121 genome-wide significant gene-trait pairs. Our study presents a comprehensive map of noncoding rare variant associations in both disease and biomarker domains. Many associations were undetected in prior exome- or array-based studies and were enriched in drug targets and biologically coherent pathways. All results are publicly accessible through an interactive portal (https://www.staarphewas.org/), offering a foundational resource for rare variant discovery, functional interpretation, and translational genomics.