HERC2

HERC2 encodes a large HECT-domain E3 ubiquitin ligase, but the well-studied pigmentation effect comes from a regulatory element within its intron 86 that acts as a long-range enhancer for the neighboring OCA2 gene, looping to the OCA2 promoter to control melanin production in melanocytes. The variant rs12913832 in this HERC2 regulatory region is the single strongest determinant of blue versus brown eye color: the ancestral A allele promotes OCA2 expression and darker pigmentation, while the derived G allele reduces OCA2 expression, producing blue eyes and lighter overall pigmentation.