rs1800407 — OCA2 Arg419Gln

The Green-Eyed Gene — How a Single Amino Acid Shapes Eye Color

Your eyes get their color from melanin, the same pigment that determines skin tone. But eye color isn't just about how much melanin you make—it's also about how efficiently your cells can package it¹¹ how efficiently your cells can package it
Melanin is produced in specialized organelles called melanosomes within melanocytes, and the efficiency of this process depends on precise pH regulation. The OCA2 gene encodes the P protein, a melanosomal transporter that regulates the pH environment where melanin is synthesized²² regulates the pH environment where melanin is synthesized
The P protein is a chloride channel that shifts melanosomal pH from acidic to neutral, which is essential for tyrosinase enzyme activity. When this system works at full capacity, you get deeply pigmented brown eyes. When a variant reduces its efficiency, the result can be lighter shades—including the distinctive green and hazel hues.

rs1800407 is one such variant. This SNP changes a single amino acid in the P protein (arginine to glutamine at position 419), creating a hypomorphic version³³ hypomorphic version
A hypomorphic allele produces a partially functional protein—not completely broken, but less efficient than normal that reduces melanin production in the iris. Unlike the famous HERC2 rs12913832 variant⁴⁴ HERC2 rs12913832 variant
The HERC2 rs12913832 SNP is the primary determinant of blue vs. brown eyes in Europeans, but rs1800407 in OCA2 acts as a penetrance modifier that primarily controls blue versus brown eyes, rs1800407 is the strongest genetic predictor of intermediate eye colors—green, hazel, and light brown.

The Mechanism

The OCA2 gene sits on chromosome 15 and encodes an 838-amino-acid transmembrane protein localized to melanosomes. The P protein functions as a chloride-selective anion channel⁵⁵ chloride-selective anion channel
OCA2-mediated chloride efflux from the melanosome lumen reduces proton pump activity, raising organellar pH that modulates the pH of these pigment-producing organelles. Early-stage melanosomes are highly acidic (pH < 6.0), but tyrosinase⁶⁶ tyrosinase
the rate-limiting enzyme in melanin synthesis | is inactive below pH 6.0. To produce melanin, the melanosome must neutralize its pH—and that's where OCA2 comes in.

By transporting chloride ions out of the melanosome, the P protein counterbalances proton pumps and shifts pH toward neutral. This creates the optimal environment for tyrosinase to convert tyrosine into melanin. The Arg419Gln substitution⁷⁷ Arg419Gln substitution
rs1800407 changes CGG (arginine) to CAG (glutamine) in exon 13 reduces the efficiency of this chloride transport, resulting in a more acidic melanosomal environment and reduced melanin synthesis.

Importantly, rs1800407 doesn't act alone. It sits in strong linkage disequilibrium⁸⁸ linkage disequilibrium
two genetic variants that are inherited together more often than expected by chance with HERC2 rs12913832, a regulatory variant 21 kb upstream that controls OCA2 transcription. The HERC2 variant acts as an enhancer that determines whether OCA2 is expressed at all, while rs1800407 determines how efficiently the protein works once it's made. When both variants are present—the HERC2 A allele reducing OCA2 expression and the rs1800407 A allele producing a hypomorphic protein—the combined effect on pigmentation is stronger than either alone.

The Evidence

Andersen et al. (2016)⁹⁹ Andersen et al. (2016)
Importance of nonsynonymous OCA2 variants in human eye color prediction. Mol Genet Genomic Med 4:420-430 identified rs1800407 as one of three nonsynonymous OCA2 variants critical for eye color prediction. In a sample of 1,570 Danish individuals, a four-variant haplotype (HERC2 rs12913832 + three OCA2 coding variants including rs1800407) explained 75.6% of eye color variation (adjusted R² = 0.76), compared to 68.8% for rs12913832 alone. The rs1800407 A allele showed the strongest association with green and hazel eye colors.

Branicki et al. (2008)¹⁰¹⁰ Branicki et al. (2008)
Association of polymorphic sites in the OCA2 gene with eye colour using the tree scanning method. Ann Hum Genet 72:184-192 used an evolutionary tree scanning approach to identify rs1800407 as the single strongest OCA2 predictor of eye color variation. Among individuals with the HERC2 rs12913832 AA genotype (predisposed to blue eyes), the penetrance of green/hazel eyes was 50% for rs1800407 AA, 21% for AG, and 6% for GG.

Donnelly et al. (2012)¹¹¹¹ Donnelly et al. (2012)
A global view of the OCA2-HERC2 region and pigmentation. Hum Genet 131:683-696 genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region. The rs1800407 A allele is geographically restricted, reaching frequencies of 0-11% in Europe, 0-9.4% in Southwest Asia, and 0-9.3% in Central Asia, with highest frequencies in Northern Europe. Outside these regions, it's rare (1-4% in some Native American and African American populations, <1% in East Asia and Africa). Long-range haplotype tests provided evidence of positive selection in Europe, consistent with the hypothesis that lighter pigmentation was advantageous at higher latitudes.

rs1800407 also affects skin pigmentation. The same Andersen study¹²¹² Andersen study found that two OCA2 coding variants, including those in linkage with rs1800407, had measurable effects on quantitative skin color. This makes biological sense: OCA2 regulates melanosome pH in all melanocytes, not just those in the iris.

There's also evidence linking rs1800407 to melanoma risk. Guedj et al. (2013)¹³¹³ Guedj et al. (2013)
Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree. Hum Mutat 34:333-339 reported that the rs1800407 A allele was a significant risk factor for cutaneous malignant melanoma in a GWAS (OR 1.27, p=0.0006). This association likely reflects the reduced melanin content in skin and eyes, which provides less photoprotection against UV radiation.

Practical Actions

If you carry the A allele, you likely have lighter eye color (green, hazel, or light brown) and possibly lighter skin tone than your GG counterparts. This has implications for UV protection¹⁴¹⁴ UV protection
Melanin absorbs and dissipates UV radiation, preventing DNA damage. With less melanin in your skin and eyes, you have reduced natural photoprotection and should prioritize sun safety—especially if you also carry blue-eye alleles at HERC2 rs12913832.

Beyond pigmentation, this variant is a reminder of how tightly regulated biological systems are. Melanosome pH must be precisely controlled to balance competing demands: acidic enough to prevent premature melanin polymerization, but neutral enough for tyrosinase to function. A single amino acid change at position 419 tips this balance, producing not just a different eye color, but a slightly different melanin profile throughout your body.

Interactions

rs1800407 shows strong epistatic interactions with HERC2 rs12913832¹⁵¹⁵ HERC2 rs12913832
A regulatory variant in an enhancer region 21 kb upstream of OCA2 that controls OCA2 gene expression. The HERC2 variant determines how much OCA2 protein is produced, while rs1800407 determines how well that protein functions. When both the HERC2 rs12913832 A allele (reduced OCA2 expression) and the rs1800407 A allele (hypomorphic P protein) are present in cis (on the same chromosome), the combined effect on pigmentation is greater than additive. Haplotype analyses show that the doubly-derived haplotype (HERC2 A + OCA2 A) is especially common in Northern Europe and strongly associated with green and hazel eye colors.

rs1800407 also interacts with other OCA2 coding variants. Andersen et al.¹⁶¹⁶ Andersen et al. identified rs74653330 (p.Ala481Thr) and rs121918166 (p.Val443Ile) as additional nonsynonymous OCA2 variants that contribute to eye color variation when present with rs1800407. These variants likely affect different functional domains of the P protein, and when combined, they produce an even broader spectrum of intermediate eye colors.

There's also evidence for gene-gene interactions beyond OCA2. Studies have found synergistic interactions between HERC2 rs12913832 and TYRP1 rs1408799¹⁷¹⁷ TYRP1 rs1408799
tyrosinase-related protein 1, another enzyme in the melanin synthesis pathway in determining green eye color. The prediction accuracy for green eyes increases from AUC 0.667 to 0.697 when these interactions are modeled. This suggests that the final eye color phenotype emerges from a network of interacting variants across multiple pigmentation genes.