Structural divergence of G6PD variants shapes red blood cell storage and transfusion performance

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy, yet how donor alleles shape red blood cell (RBC) storage, transfusion performance, and recipient physiology remains unresolved. Across 13,091 donors, a recalled cohort, donor-recipient data, humanized mice, and a prospective sickle cell disease cohort, variants reduced G6PD abundance, constrained pentose phosphate pathway flux and redox metabolism, and accelerated age-dependent functional decay. Murine A-; RBCs recovered poorly; A-; and Mediterranean RBCs impaired renal oxygenation, especially the latter, which caused greater plasma hemolysis. In humans, A-; units yielded smaller hemoglobin increments, while deficient units reduced allogeneic 51Cr post-transfusion recovery and four-week survival by 8 and 12-percentage-points. NADP;-bound cryo-EM resolved mechanisms: remodeling of the catalytic NADP;-binding region and dimer interface underlies A-; kinetic fragility, whereas Mediterranean S188F exhibits temperature-dependent oligomerization and conformational instability. These findings define an allelic series linking genotype to molecular instability, RBC quality, transfusion performance, and recipient physiology.