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

Introduction: variants offers opportunities to enhance awareness of its pharmacological relevance, particularly across different ancestral groups. Methods: alleles with ClinVar "undefined" significance classifications were cross-referenced with expert pharmacological resources [e.g., Pharmacogene Variation (PharmVar) Consortium] to identify candidates for reclassification as "drug response" significance variants. Results: 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 levels in PharmVar. Conclusion: alleles across ancestral subgroups. These insights support potential reclassification of certain "undefined" alleles and highlight the importance of inclusive pharmacogenomic research to improve population-specific drug response knowledge.