386 Opportunities to improve open All of Us data to convey CYP2D6 pharmacological relevance and interpretation overall and according to ancestry

Objectives/Goals: CYP2D6 is a highly polymorphic gene with significant pharmacogenomic and public health implications. Understanding the population distribution of CYP2D6 variants offers opportunities to enhance awareness of its pharmacological relevance, particularly across different ancestral groups. Methods/Study Population: Using the National Institute of Health All of Us Research Program Data Browser, we identified CYP2D6 alleles with a frequency ≥0.10 in the overall cohort or within ancestral subgroups and classified in ClinVar as having either “drug response” or ”undefined” significance. We assessed alleles with frequency differences ≥0.10 between ancestral subgroups and the overall population to highlight subgroup-specific pharmacogenomic relevance. CYP2D6alleles with ClinVar “undefined” significance classifications were cross-referenced with expert pharmacological resources (e.g., PharmVar) to identify candidates for reclassification as ”drug response” significance variants. Results/Anticipated Results: Among the 89CYP2D6 alleles with ClinVar “drug response” significance classification, 7 of 11 (64%) were more frequent (≥ 0.10) in the East Asian ancestry subgroup compared to the overall population. Among 6,262 CYP2D6 alleles with “undefined” significance classification, 60 showed elevated frequencies (≥ 0.10) in at least one subgroup: Middle Eastern (31/60; 52%), African (22/60; 37%), East Asian (21/60; 35%), and South Asian (4/60; 7%) ancestries. Of these 60 alleles, 16 (27%) map to 41–76, star allele haplotypes that contain at least one sub-allele with “definitive” allele evidence level in PharmVar. Discussion/Significance of Impact: Our findings highlight the differential distribution and potential pharmacological relevance of CYP2D6 alleles across ancestral subgroups. These insights support potential reclassification of certain ”undefined” alleles and highlight the importance of inclusive pharmacogenomic research.