rs6058017 — ASIP A8818G

3'UTR variant controlling ASIP protein output; G allele reduces ASIP mRNA 12-fold, promoting eumelanin and darker skin, hair, and eye pigmentation

See your personal result for ASIP

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

The Pigmentation Dimmer Switch — ASIP and the Eumelanin/Pheomelanin Balance

Your skin color is not simply on or off — it is the result of a molecular competition between two opposing signals in every melanocyte. On one side is α-melanocyte stimulating hormone (α-MSH), which binds the melanocortin-1 receptor (MC1R) and drives eumelanin (brown-black pigment) production. On the other side is agouti signaling protein (ASIP), a secreted antagonist that blocks MC1R and pushes melanocytes toward pheomelanin (red-yellow pigment). The rs6058017 variant in ASIP — located 25 bases downstream of the gene's stop codon in the 3' untranslated region — is a key dial controlling how much ASIP protein your melanocytes produce, and therefore how dark your constitutive pigmentation tends to be.

The Mechanism

The rs6058017 A>G substitution lies in the 3' untranslated region (3'UTR) of ASIP — the tail of the messenger RNA that controls transcript stability, translation efficiency, and protein output. The G allele (ancestral, more common in African populations) causes premature mRNA degradation and message instability11 premature mRNA degradation and message instability
Voisey et al., 2006, quantitative RT-PCR in human skin biopsies. Cells carrying the AA genotype produce roughly 12 times more ASIP mRNA than cells carrying the AG genotype, meaning AA individuals flood their melanocytes with ASIP protein that actively suppresses eumelanin synthesis. In contrast, G allele carriers have less ASIP, leaving MC1R signaling relatively unopposed — α-MSH can bind freely, activate cAMP cascades, upregulate MITF and tyrosinase, and drive robust eumelanin production. The result is a genetically encoded tendency toward darker skin, hair, and eye color in G allele carriers.

The A allele, which rose to high frequency in European populations through positive selection, increases ASIP expression and tips the balance toward pheomelanin synthesis. Because pheomelanin provides substantially less UV photoprotection than eumelanin — and may even generate reactive oxygen species under UV irradiation that compound DNA damage — individuals with the AA genotype carry a constitutional vulnerability to ultraviolet injury despite appearing to have "normal" European-type skin.

The Evidence

The pigmentation associations of rs6058017 were first reported by Kanetsky et al. in 200222 Kanetsky et al. in 2002
147 healthy Caucasian controls at the University of Pennsylvania, melanoma cases excluded. Carriage of the G allele was significantly associated with dark hair (OR 1.8, 95% CI 1.2–2.8) and brown eyes (OR 1.9, 95% CI 1.3–2.8) after adjustment for age and sex. Homozygous GG carriers showed an even stronger signal, though the small GG sample (n=9) limited statistical power. The functional basis for this association was established by Voisey et al. in 200633 Voisey et al. in 2006
Australian European and indigenous Australian skin biopsies, who used quantitative RT-PCR to demonstrate the 12-fold difference in mRNA abundance between AA and AG genotypes. The same study found the G allele significantly more frequent in indigenous Australians than European Australians, consistent with the ancestral nature of the G variant. A complementary study by Bonilla et al. in 200544 Bonilla et al. in 2005
234 African Americans, skin reflectometry confirmed that the 8818G allele was associated with darker objectively measured skin color, with particularly pronounced effects in women (P<0.001).

An important distinction: rs6058017 itself has a weak and inconsistent association with melanoma risk across studies — some show modest association, others show null results. The strong skin cancer signal in the ASIP locus comes from a separate upstream haplotype defined by rs1015362 and rs491141455 upstream haplotype defined by rs1015362 and rs4911414
located ~110 kb upstream of ASIP coding sequence, which reached genome-wide significance for cutaneous melanoma (OR 1.45, P=1.2×10⁻⁹) and BCC (OR 1.33, P=1.2×10⁻⁶) in 2,121 melanoma cases and over 40,000 controls. This haplotype is not in strong linkage disequilibrium with rs6058017 — the two signals are partially independent. Individuals with the rs6058017 A allele carry lighter pigmentation and the biologic rationale for elevated UV risk, but direct attribution of melanoma risk to this specific variant requires additional study.

Practical Implications

Your ASIP genotype shapes your constitutive (baseline) pigmentation level, which in turn determines how much photoprotection your skin's melanin provides against UV-induced DNA damage. Individuals with the AA genotype produce more ASIP, suppress eumelanin synthesis, and tend toward lighter skin that offers less natural UV shielding. The practical implication is dose-dependent UV protection regardless of whether you tan easily: broad-spectrum SPF 30+ sunscreen daily, protective clothing when outdoors for extended periods, and annual dermatologic skin checks for those with multiple light-pigmentation variants.

The GG genotype, more common in people of West African, South Asian, and East Asian ancestry, reflects ancestrally high ASIP suppression — producing constitutively darker, more photoprotective eumelanin-rich skin. This does not eliminate melanoma risk entirely (acral and mucosal melanomas occur across pigmentation types), but the UV-driven pathway to cutaneous melanoma is substantially less active.

Interactions

The most clinically relevant interaction is between ASIP and MC1R. ASIP acts as an endogenous competitive antagonist at MC1R — so variants that weaken MC1R signaling (such as rs1805007 R151C and rs1805008 R160W, associated with red hair) interact with ASIP variants in compound fashion: both reduce eumelanin output through different mechanisms. Individuals carrying the ASIP AA genotype (high ASIP, low eumelanin) together with MC1R red-hair-color variants (impaired MC1R, reduced cAMP response to α-MSH) face a dual eumelanin deficit that may substantially amplify UV vulnerability and melanoma risk. This interaction is worth noting for those with both a pale, poorly-tanning complexion and a family history of melanoma — the compound genotype warrants more aggressive photoprotection and surveillance.

Within the ASIP locus, the relationship between rs6058017 and the upstream haplotype (rs1015362, rs4911414) is also important to understand: these signals are partially independent, and individuals carrying both the ASIP haplotype risk alleles AND the rs6058017 A allele may carry compounded risk through distinct molecular mechanisms at the same locus.

Genotype Interpretations

What each possible genotype means for this variant.

GG Low ASIP Output Beneficial

Low ASIP protein maximizes eumelanin production — greater natural UV photoprotection

The eumelanin produced in response to low ASIP levels provides two layers of UV protection: it acts as a broadband UV absorber, attenuating UV penetration into the epidermis; and eumelanin itself has significant antioxidant capacity that neutralizes reactive oxygen species generated by UV photons that do penetrate. In contrast, pheomelanin (dominant in AA individuals) not only absorbs UV poorly but can generate ROS under UV exposure, compounding DNA damage rather than mitigating it.

Research in Australian Aboriginal populations and West African cohorts confirms substantially higher G allele frequencies than in European-ancestry populations, consistent with the ancestral origin of this variant. The Bonilla et al. 2005 study in African Americans directly measured skin reflectance and found the GG and AG genotypes associated with objectively darker skin color (P=0.01 for ASIP genotype effect), particularly in women.

Note: while this genotype is beneficial in terms of UV photoprotection, screening awareness for melanoma subtypes not driven by UV (acral, mucosal) remains important for all individuals.

AG Intermediate ASIP Output Intermediate

One G allele reduces ASIP output moderately, producing intermediate pigmentation

The additive inheritance pattern of this variant means AG heterozygotes show phenotypes genuinely intermediate between AA and GG homozygotes. In the original Kanetsky 2002 study, G allele carriers (AG + GG combined) showed meaningful associations with dark hair and brown eyes, though the GG homozygotes showed stronger effects. This dosage relationship confirms that each G allele incrementally suppresses ASIP mRNA and protein, allowing progressively more eumelanin synthesis.

UV sensitivity in AG individuals is intermediate — they tend to tan more readily than AA individuals but may still burn with prolonged unprotected UV exposure. The practical implication is that while constitutive photoprotection is better than in AA individuals, it is not at the level of GG homozygotes, and sun protection remains important, particularly during intense UV exposure.

AA High ASIP Output High Risk

High ASIP expression suppresses eumelanin — lighter pigmentation and reduced UV photoprotection

The mechanistic basis for this genotype's effect is well-established. The A allele maintains ASIP mRNA stability through standard 3'UTR function, while the G variant disrupts this stability and leads to premature degradation. Quantitative RT-PCR studies show the magnitude of this difference is approximately 12-fold in mRNA abundance between AA and AG genotypes — a large functional effect for a non-coding variant.

At the phenotypic level, population studies consistently show that AA homozygotes are more likely to have lighter hair, lighter eyes, and lighter skin than G allele carriers, independent of other pigmentation loci. The effect is not deterministic — dozens of genes contribute to human pigmentation — but this variant contributes a meaningful nudge toward lighter phenotypes, especially in populations where multiple light-pigmentation variants co-occur.

The direct melanoma association of rs6058017 AA genotype is inconsistent across studies (some show modest elevation, others null), so it is best understood as a pigmentation modulator with indirect implications for UV risk rather than a direct melanoma susceptibility variant.