Natural form of vitamin D produced in the skin from sunlight — significantly more effective than D2 at raising and maintaining serum 25(OH)D levels. Converted in the liver to 25(OH)D, then in the kidney and peripheral tissues to calcitriol (active form), which binds the Vitamin D Receptor (VDR) and regulates expression of hundreds of genes involved in calcium transport (TRPV6), bone remodeling, immune modulation, and inflammatory signaling. VDR variants reduce receptor sensitivity — D3 provides more circulating calcitriol substrate to maintain consistent gene-level signaling despite partial receptor impairment. This is substrate optimization, not VDR correction.