rs16891982 — SLC45A2 L374F

The Pigmentation Gene That Shapes Melanoma Risk

SLC45A2 encodes a melanosomal membrane transporter protein previously known as MATP¹¹ previously known as MATP
membrane-associated transporter protein that regulates melanin synthesis by controlling melanosomal pH through proton transport. The L374F variant (rs16891982) represents one of the most important genetic determinants of pigmentation variation in human populations, with the derived F374 allele nearly fixed in Northern Europeans but rare or absent in African and East Asian populations. This variant exemplifies the evolutionary trade-off²² evolutionary trade-off
lighter skin enhances vitamin D synthesis at high latitudes but reduces photoprotection between adaptive depigmentation for vitamin D synthesis in low-UV environments and protection against UV-induced skin damage.

The Mechanism

The L374F substitution changes a leucine to phenylalanine at position 374 of the SLC45A2 protein. This missense variant alters the protein's ability to maintain optimal melanosomal pH, which is critical for tyrosinase activity—the rate-limiting enzyme in melanin production. The ancestral L374 allele maintains an optimal pH environment for maximal eumelanin (brown-black pigment) synthesis, while the derived F374 allele creates a more acidic melanosomal environment that negatively affects tyrosinase activity³³ negatively affects tyrosinase activity
reduced pH impairs copper binding to tyrosinase, leading to lighter pigmentation. Individuals carrying two copies of the F374 allele produce significantly less melanin, resulting in paler skin, lighter hair, and increased sun sensitivity.

The Evidence

The protective role of the C allele (F374) against melanoma was first identified in a Spanish case-control study of 131 melanoma patients⁴⁴ Spanish case-control study of 131 melanoma patients
OR 0.41, 95% CI 0.24-0.70, P=0.008. This finding has been robustly replicated across multiple populations. A meta-analysis of three South European populations⁵⁵ meta-analysis of three South European populations
1,639 melanoma cases and 1,342 controls confirmed the F374L variant as strongly protective for melanoma (OR 0.41, 95% CI 0.33-0.50, P=3.50×10⁻¹⁷), with the protective effect persisting even after adjustment for clinical confounders. A comprehensive field synopsis and meta-analysis⁶⁶ comprehensive field synopsis and meta-analysis
genome-wide statistical significance P<1×10⁻⁷ identified SLC45A2 at 5p13.2 as one of only four loci with genome-wide significant association with cutaneous melanoma and strong epidemiological credibility.

Conversely, the ancestral L374 allele (G) is strongly associated with dark pigmentation. In a European population study⁷⁷ European population study
OR 7.05 for black hair, the L374 allele significantly increased the likelihood of having black hair color. A Spanish population analysis of 558 individuals⁸⁸ Spanish population analysis of 558 individuals
statistically significant correlation P<0.001 revealed that L374F allele frequency correlated with incident UV radiation intensity, with the 374F allele more frequent in lighter-skinned individuals. Remarkably, the homozygous L374/L374 genotype was absent in all 119 melanoma samples⁹⁹ absent in all 119 melanoma samples
compared to 970 healthy controls from Spain, suggesting complete protection against melanoma development.

The F374 allele shows extreme population differentiation, with frequencies of approximately 96.5% in Germans, 88-94% in Southern Europeans, 61.5% in Turks, but only 14.7% in South Asians and 5.9% in Bangladeshis, and essentially absent in African populations¹⁰¹⁰ essentially absent in African populations
<6% frequency. This distribution pattern indicates recent positive selection¹¹¹¹ recent positive selection
evidence from haplotype analysis and neutrality tests favoring lighter pigmentation in European populations over the past 5,000-20,000 years.

Practical Implications

Your genotype at this position directly influences your skin's natural photoprotection capacity and melanoma risk. The paradox is straightforward: lighter skin (CC or CG genotypes) enhances vitamin D synthesis but dramatically increases vulnerability to UV-induced DNA damage and melanoma. Individuals with one or two copies of the C allele require more rigorous photoprotection than those with the GG genotype.

For CC and CG carriers, sun protection is not optional—it is a medical necessity. Use broad-spectrum sunscreen SPF 30 or higher¹²¹² broad-spectrum sunscreen SPF 30 or higher
blocks 97% of UVB rays daily on all exposed skin, reapplied every 2 hours during sun exposure. Seek shade between 10 AM and 4 PM when UV intensity peaks. Wear protective clothing including long sleeves, wide-brimmed hats, and UV-blocking sunglasses. Avoid tanning beds entirely, as they deliver concentrated UV radiation without the photoprotective adaptations that occur with gradual sun exposure.

Annual full-body skin examinations by a dermatologist are recommended for CC carriers, particularly those with additional risk factors such as fair hair, multiple nevi (moles), or a family history of melanoma. Self-examination monthly can detect suspicious lesions early—melanoma detected at stage I has a 99% five-year survival rate.

For individuals with darker constitutive pigmentation (GG genotype), melanoma risk is substantially lower but not zero. While daily sunscreen may not be medically necessary in the same way, sun protection during prolonged outdoor activities and awareness of melanoma warning signs remain important.

Interactions

SLC45A2 L374F interacts epistatically with variants in other pigmentation genes to modulate melanoma risk. The most significant interaction occurs with MC1R (melanocortin-1 receptor) variants. Individuals carrying two or more MC1R red hair color variants¹³¹³ Individuals carrying two or more MC1R red hair color variants
well-established high-risk genotypes have decreased melanoma risk if they concurrently carry the protective SLC45A2 F374 variant. This suggests that while MC1R variants increase melanoma susceptibility through impaired tanning response, the high melanin synthesis enabled by the ancestral L374 allele can partially offset this risk.

Additional interactions have been documented with OCA2, ASIP, TYR, and TYRP1 variants. A large Australian case-control study¹⁴¹⁴ large Australian case-control study
1,738 cases and 4,517 controls detected significant epistatic interactions between SLC45A2 and OCA2 alleles, and between MC1R and ASIP alleles, in modulating melanoma risk. These pigmentation loci together account for approximately 12% of familial melanoma risk in high-UV populations.

The combined effect of multiple light-pigmentation variants compounds melanoma susceptibility beyond simple additive models. Individuals carrying high-risk alleles at SLC45A2, MC1R, TYR, and OCA2 simultaneously should be considered at substantially elevated risk and prioritized for intensive photoprotection counseling and surveillance.