rs1426654 — SLC24A5 Ala111Thr

The Gene That Lightened European Skin

A single letter change in the SLC24A5 gene — replacing alanine with threonine at position 111 of the protein — is the largest known contributor to lighter skin pigmentation in humans¹¹ the largest known contributor to lighter skin pigmentation in humans
Lamason RL et al. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science. 2005. This variant alone explains 25-38% of the difference in skin melanin between people of European and West African ancestry, making it one of the most impactful genetic variants for any visible human trait.

SLC24A5 encodes a potassium-dependent sodium-calcium exchanger²² potassium-dependent sodium-calcium exchanger
NCKX5, a member of the solute carrier family that transports ions across cell membranes located on the membrane of melanosomes — the specialized compartments within skin cells where melanin is synthesized and stored. The ancestral alanine variant allows normal calcium exchange and melanin production, while the derived threonine variant reduces calcium-exchange activity, disrupting the pH balance needed for proper melanin synthesis.

The Mechanism

Melanin production requires a carefully orchestrated sequence of enzymatic reactions inside melanosomes. The key enzyme, tyrosinase, must undergo proper maturation in the trans-Golgi network³³ trans-Golgi network
a cellular sorting station that processes and packages proteins before being transported to melanosomes. This maturation process is exquisitely sensitive to pH and calcium levels.

SLC24A5 normally transports calcium out of the trans-Golgi network in exchange for sodium and potassium. When the Ala111Thr variant reduces this calcium-exchange activity, the altered calcium concentration acidifies the trans-Golgi network⁴⁴ the altered calcium concentration acidifies the trans-Golgi network
Quillen EE & Shriver MD. Unpacking human skin pigmentation. Cell. 2011, impairing tyrosinase maturation and decreasing its catalytic efficiency. The result: melanocytes produce substantially less melanin even when all the enzymatic machinery is present and functional.

Studies using zebrafish carrying the equivalent variant demonstrate this clearly — the fish develop a characteristic "golden" phenotype with dramatically reduced melanin, and the same molecular mechanism operates in human skin cells.

The Evidence

The Ala111Thr variant (rs1426654, nucleotide change G→A) is nearly fixed in European populations at 98.7-100% frequency⁵⁵ nearly fixed in European populations at 98.7-100% frequency
Crawford NG et al. Loci associated with skin pigmentation identified in African populations. Science. 2017, while the ancestral alanine form predominates at 93-100% in Sub-Saharan African, East Asian, and Indigenous American populations. This dramatic frequency difference makes rs1426654 one of the most powerful ancestry-informative markers⁶⁶ ancestry-informative markers
genetic variants that differ substantially in frequency across continental populations in the human genome.

South Asian populations show intermediate frequencies⁷⁷ South Asian populations show intermediate frequencies
Mallick CB et al. The light skin allele of SLC24A5 in South Asians and Europeans shares identity by descent. PLoS Genet. 2013 (averaging 53%, ranging from 3% to 100% across the subcontinent), and genetic dating analyses indicate the light-skin allele in Europeans and South Asians shares a common origin through identity by descent, with coalescence estimated at 22,000-28,000 years ago. The variant shows one of the strongest genomic signatures of positive selection in Europeans, consistent with rapid adaptation after ancestral populations migrated to high-latitude environments with reduced UV radiation.

In a quantitative skin pigmentation study of 1,228 South Indians, rs1426654 genotype alone explained 27% of the total variation in melanin index⁸⁸ rs1426654 genotype alone explained 27% of the total variation in melanin index
with a likelihood ratio test showing p = 2.4×10⁻³¹ and odds ratio of 26.2 for the lighter-skin allele. Among Brazilian melanoma patients and controls, the AA genotype conferred a 7-fold increased melanoma risk⁹⁹ the AA genotype conferred a 7-fold increased melanoma risk
Guimarães-Bastos D et al. Skin pigmentation polymorphisms associated with increased risk of melanoma. BMC Cancer. 2020 (OR = 7.13, 95% CI: 1.87-27.11, p < 0.01) compared to GG, consistent with the established relationship between lighter skin and UV-induced DNA damage.

Practical Actions

Your genotype at this variant determines your baseline skin pigmentation capacity, which has direct implications for UV sensitivity, vitamin D synthesis, and skin cancer risk. The genetic mechanism is clear and the effect size is large — this isn't a subtle statistical association but a fundamental determinant of how your skin responds to sunlight.

For AA genotypes (light skin variant): Your reduced melanin production means less natural UV protection. You sunburn more easily, accumulate UV-induced DNA damage more rapidly, and face elevated melanoma and non-melanoma skin cancer risk. However, your skin synthesizes vitamin D more efficiently at low UV levels, which was adaptive for ancestral populations at northern latitudes but creates a tradeoff in modern sun-exposure patterns. Rigorous sun protection is essential — broad-spectrum sunscreen (SPF 30-50), protective clothing, and UV-avoidance during peak hours. Monitor for suspicious skin changes and establish regular dermatological surveillance, especially if you have additional risk factors (fair hair, blue eyes, family history).

At the same time, lighter skin means you need less sun exposure to maintain vitamin D levels¹⁰¹⁰ less sun exposure to maintain vitamin D levels
approximately 10-15 minutes of midday sun on arms and legs, 2-3 times weekly. At latitudes above 35°N during winter months (November-March), UVB radiation is insufficient for vitamin D synthesis regardless of skin type¹¹¹¹ UVB radiation is insufficient for vitamin D synthesis regardless of skin type
Webb AR et al. Influence of season and latitude on cutaneous synthesis of vitamin D₃. J Clin Endocrinol Metab. 1988, making supplementation necessary to maintain adequate circulating 25(OH)D levels.

For GG genotypes (dark skin variant): Your higher melanin content provides substantial natural UV protection, reducing sunburn susceptibility and skin cancer risk. However, melanin also absorbs UVB radiation before it can trigger vitamin D synthesis — people with very dark skin may require up to 10 times longer sun exposure¹²¹² up to 10 times longer sun exposure
to produce equivalent vitamin D levels compared to fair-skinned individuals. At high latitudes or during winter, this can make it nearly impossible to maintain adequate vitamin D through sun exposure alone. Year-round vitamin D supplementation (1000-2000 IU daily, or higher if blood tests confirm deficiency) is advisable, particularly if you live far from the equator.

For AG genotypes (intermediate): You have moderate melanin production — better UV protection than AA homozygotes but less than GG, and intermediate vitamin D synthesis efficiency. Standard sun protection practices apply (SPF 30, reapplication every 2 hours, protective measures during peak UV), and vitamin D status should be monitored through blood testing, with supplementation adjusted accordingly.

Interactions

SLC24A5 is part of a broader polygenic architecture controlling human pigmentation. While rs1426654 is the single largest contributor, it interacts with variants in other pigmentation genes to determine your overall skin, hair, and eye color phenotype.

SLC45A2 rs16891982¹³¹³ SLC45A2 rs16891982
another sodium-calcium exchanger variant, p.Leu374Phe is the second-largest contributor to European skin lightening and shows strong epistatic interaction with SLC24A5¹⁴¹⁴ shows strong epistatic interaction with SLC24A5
individuals homozygous for derived alleles at both loci have lighter skin than predicted from additive effects. Similarly, TYR rs1042602¹⁵¹⁵ TYR rs1042602
the gene encoding tyrosinase itself, p.Ser192Tyr and OCA2/HERC2 rs12913832¹⁶¹⁶ OCA2/HERC2 rs12913832
the master regulator of eye color contribute additional variation, and simultaneous genotyping of rs1426654, rs16891982, and rs1042602 has been validated for forensic pigmentation prediction¹⁷¹⁷ simultaneous genotyping of rs1426654, rs16891982, and rs1042602 has been validated for forensic pigmentation prediction
Soejima M et al. Simultaneous genotyping of three SNVs involved in skin pigmentation. Hum Mutat. 2025.

The combined effect of these variants determines not only baseline pigmentation but also your capacity to tan (facultative pigmentation) and how your skin ages under UV exposure. If you carry light-skin variants at multiple loci, the cumulative effect on UV sensitivity and cancer risk is greater than any single variant alone — making comprehensive sun protection even more critical.

From an evolutionary perspective, SLC24A5 illustrates how human populations balanced competing selective pressures¹⁸¹⁸ human populations balanced competing selective pressures
the vitamin D-folate hypothesis during migrations out of Africa. At equatorial latitudes, dark skin protects folate from UV-induced photolysis (critical for DNA synthesis and fetal development), while at high latitudes, lighter skin facilitates vitamin D synthesis under low-UV conditions (essential for calcium homeostasis and immune function). The rapid selective sweep of rs1426654 in Europeans reflects strong positive selection for this physiological tradeoff in novel UV environments.