PROJECT SUMMARY Variants of uncertain significance (VUS) pose many problems in the delivery of genomic medicine, as they are hard to interpret for clinicians and confusing for patients. One important piece of evidence that can be used to reclassify VUS is case/control data; an enrichment of a particular variant in patients with a specific disease (generally already known to be related to the gene in which the variant occurs) is strong evidence for pathogenicity of that variant. The All of Us research program is assembling a cohort with unprecedented diversity that combines genetic data with electronic health records (EHR). This creates the opportunity to examine many VUS that have never been seen before, and explore the utility of the EHR data to build sets of AoU participants that fall into case and control groups. This project will thus inform variant classification, but also create a toolset for the researcher workbench that is currently missing: the ability to sift through and prioritize clinically-relevant variants. Additionally, data collected in this study will likely bear on health disparities. Previous studies have shown that pathogenic variants are distributed differently among groups with different ancestry backgrounds. The same is likely to be true for VUS, especially in understudied populations. Collecting data on VUS prevalence will allow the targeting of future efforts aimed at reducing these disparities.