DPYD encodes dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in pyrimidine base catabolism that catalyzes the reduction of uracil and thymine. The enzyme also metabolizes the chemotherapeutic drug 5-fluorouracil, a critical determinant of drug safety and efficacy. Individuals with DPYD loss-of-function variants have markedly impaired fluoropyrimidine metabolism, resulting in drug accumulation and severe, potentially life-threatening toxicities including myelosuppression, mucositis, diarrhea, and hand-foot syndrome 1. Prospective DPYD genotyping for four key variants (DPYD*2A, c.1679T>G, c.2846A>T, and c.1236G>A) enables dose individualization and substantially reduces severe toxicity: a 50% initial dose reduction for DPYD*2A and c.1679T>G carriers reduced the relative risk of severe toxicity from 2.87 and 4.30 to 1.31 and near-zero, respectively 2. In patients with gastrointestinal cancer receiving genotype-guided dosing, actionable DPYD variants were associated with a 90% lower risk of clinically relevant toxicity compared to standard care 3. Clinical implementation of DPYD genotyping prior to fluoropyrimidine initiation is now considered essential standard of care 4. At the population level, gnomAD v4.1 classifies DPYD as loss-of-function tolerant (LOEUF=1.09), yet this gene harbors 146 pathogenic variants in ClinVar, reflecting the distinction between population-level constraint and clinical pathogenicity in cancer therapeutics.