CYP2R1 encodes a cytochrome P450 monooxygenase that functions as the principal hepatic 25-hydroxylase in vitamin D metabolism 12. The enzyme catalyzes hydroxylation at the C-25 position of both vitamin D2 and D3, converting parent vitamin D to 25-hydroxyvitamin D (25(OH)D), the major circulating biomarker of vitamin D status 3. CYP2R1 also metabolizes vitamin D analogs including doxercalciferol and alfacalcidol. Mechanistically, the enzyme uses molecular oxygen to insert one atom into substrate while reducing the second to water, with electrons supplied by NADPH via cytochrome P450 reductase 2. Genetic variants in CYP2R1, particularly the rs10741657 polymorphism, significantly influence circulating 25(OH)D levels across populations 4. The G allele associates with reduced 25(OH)D levels and increased vitamin D deficiency risk 4. Loss-of-function CYP2R1 mutations cause vitamin D-dependent rickets type 1B (VDDR1B), a rare inherited disorder characterized by impaired vitamin D activation and rickets despite normal kidney function 3. CYP2R1 polymorphisms are also associated with hypertension risk, particularly when combined with obesity 5, and with coronary artery disease susceptibility 6. These findings underscore CYP2R1's critical role in vitamin D homeostasis and its importance as a genetic modifier of vitamin D-related disease risk.