rs1871534 — SLC39A4 Leu372Val

Common missense variant in the primary intestinal zinc transporter ZIP4; the Val372 allele (C on the plus strand) reduces ZIP4 surface expression and zinc uptake capacity and reached near-fixation in West Africa through positive selection, likely via pathogen-zinc-starvation advantages; the Leu372 form (G allele) is standard in European and Asian populations.

See your personal result for SLC39A4

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.

SLC39A4 Leu372Val — The World's Most Population-Differentiated Common SNP

Every milligram of zinc you absorb from food passes through a single gateway in the intestinal wall: a protein called ZIP411 ZIP4
Zinc-Iron transporter Protein 4, encoded by SLC39A4 on chromosome 8q24.3; expressed at the apical membrane of duodenal and jejunal enterocytes; the sole high-capacity zinc importer in the mammalian gut. When ZIP4 stops working entirely — through rare pathogenic mutations — the result is acrodermatitis enteropathica, a severe inherited zinc deficiency disease. But rs1871534 is not one of those rare mutations. It is one of the most common SNPs in the human genome, and its story is one of the most striking examples of recent positive selection in human evolution.

The rs1871534 variant swaps a leucine for a valine at position 372 of the ZIP4 protein (Leu372Val). The valine form — the C allele on the plus strand — is carried by essentially every person of West African descent and by virtually nobody of European or East Asian ancestry. The [FST | a measure of population differentiation ranging from 0 (identical frequency) to 1 (completely different); values above 0.90 are extremely rare for common SNPs] between Europeans and Yorubans (West Africans) for this variant is 0.99999977 — the most differentiated common SNP in the genome at the time of its discovery.

The Mechanism

Engelken et al. (2014)22 Engelken et al. (2014) investigated why this SNP shows such extreme population differentiation. They expressed both the Leu372 and Val372 forms of ZIP4 in HeLa cells and measured three outcomes: protein levels at the cell surface, baseline intracellular zinc, and zinc uptake rate. Val372 (the West African form) showed significantly reduced surface expression, lower basal intracellular zinc, and reduced zinc uptake compared to Leu372. The variant does not eliminate ZIP4 function — it reduces its efficiency.

ZIP4 is regulated through zinc-dependent endocytosis: when zinc is abundant, ZIP4 is pulled off the cell surface and degraded; when zinc is scarce, ZIP4 is rapidly trafficked back to the apical membrane to capture more zinc. The Leu372Val substitution sits in a transmembrane domain of the protein and appears to alter the protein's stability at the cell surface — [effectively reducing the maximum capacity of the intestinal zinc absorption system | Wang et al. 2004 showed that reduced surface expression is the primary mechanism by which ZIP4 missense variants impair transport (PMID 14709598)].

The Evidence

The key study is the 2014 analysis by Engelken and colleagues33 Engelken and colleagues
Engelken J et al. Extreme population differences in the human zinc transporter ZIP4 (SLC39A4) are explained by positive selection in Sub-Saharan Africa. PLoS Genet, 2014. Using coalescent simulations that accounted for local recombination hotspots, they demonstrated that the extreme allele frequency differences cannot be explained by genetic drift alone — directional selection favoring the Val372 allele in sub-Saharan Africa with a selection coefficient of approximately 0.5% is the most parsimonious explanation. This is a modest but sustained selective advantage, consistent with the allele rising to near-fixation over thousands of generations.

Why would reduced zinc absorption be advantageous? Zinc is essential for many bacterial and parasitic pathogens. The human immune system uses zinc-starvation as a front-line antimicrobial weapon — macrophages deliberately flood zinc into vesicles containing intracellular bacteria to kill them. The authors hypothesize that reduced intestinal zinc uptake by Val372-ZIP4 may also reduce systemic zinc availability to pathogens, conferring a survival advantage in high-pathogen-burden environments like sub-Saharan Africa. This hypothesis remains speculative — no direct in vivo evidence in humans has yet tested it — but it is consistent with the geographic distribution of selection and with what is known about nutritional immunity.

The functional consequence for the individual: Val372/Val372 (CC) homozygotes absorb zinc less efficiently than Leu372/Leu372 (GG) carriers. At typical dietary zinc intakes this may not produce frank deficiency, but it creates a narrower margin — particularly on high-phytate diets that already impair zinc bioavailability.

Practical Actions

For CC carriers (almost exclusively of West African or recent African ancestry), the gap between dietary zinc intake and actual absorption is wider than for GG carriers. Phytate-rich staple diets — common in sub-Saharan Africa — compound this by further reducing bioavailability. The most direct interventions are dietary: prioritise animal-source zinc (which bypasses phytate inhibition) and reduce phytate intake through food preparation techniques. Monitoring serum zinc provides an objective check on zinc adequacy.

For CG heterozygotes, a modest intermediate effect on ZIP4 surface expression is expected; the practical relevance is smaller but the same dietary principles apply.

Interactions

With SLC30A1 (ZnT1, rs3738198): ZIP4 handles zinc import at the apical membrane; ZnT1 handles export at the basolateral membrane. Individuals carrying reduced-function alleles at both transporters face a double constraint on net zinc delivery to the portal circulation.

With dietary phytate: The gene-diet interaction is the dominant modifiable factor. Phytate in legumes, wholegrains, and maize-based staples forms insoluble zinc-phytate complexes in the gut, reducing absorption to 10–15% vs 25–40% for animal-source zinc. For CC carriers, this interaction is clinically meaningful — phytate in the context of reduced ZIP4 capacity compounds into significant functional zinc inadequacy.

With pathogenic SLC39A4 variants: Compound heterozygosity — one Leu372Val allele plus one pathogenic acrodermatitis enteropathica allele on the other chromosome — has not been systematically studied but is theoretically possible. Because the pathogenic variants (p.Arg95Cys, p.Gln278His, etc.) cause null or near-null ZIP4 function, the Leu372Val allele would provide residual function on that chromosome.

Nutrient Interactions

zinc reduced_absorption

Genotype Interpretations

What each possible genotype means for this variant.

GG High-Efficiency Transporter Normal

Leu372 homozygote — standard ZIP4 zinc absorption capacity

The G allele encodes leucine at position 372 in the ZIP4 protein. This form of the transporter maintains full surface expression and maximum zinc uptake capacity. The Engelken et al. (2014) cell-culture experiments showed that Leu372-ZIP4 has higher cell-surface protein levels, higher basal intracellular zinc, and greater zinc uptake rates compared to the Val372 (C allele) form.

At the population level, the G allele is near-universal in Europe (99.5%) and East Asia (essentially 100%), having been present at high frequency in these populations for tens of thousands of years. West African populations, by contrast, have been subject to directional selection that drove the C (Val372) allele to near-fixation over the past several thousand generations.

Standard dietary zinc intake (8 mg/day for women, 11 mg/day for men) is designed with the population distribution in mind. GG carriers operate at the upper end of the ZIP4 efficiency distribution.

CG Intermediate Transport Intermediate

One Val372 allele — modest reduction in ZIP4 surface expression

The Val372 allele (C) reduces ZIP4 surface expression and zinc uptake in cell culture; heterozygotes carrying one copy are expected to have intermediate transport capacity between GG (full) and CC (reduced). Because the effect is codominant, the one-copy reduction is real but smaller than the two-copy state.

At the population level, the Val372 allele reached near-fixation in West African populations through positive selection — possibly through pathogen-zinc-starvation immunity advantages — rather than through any nutritional harm. Heterozygosity in admixed populations reflects the population history of recent African-European or African-Latin American admixture. For most people with a varied modern diet, the modest reduction in ZIP4 efficiency at one allele is unlikely to produce measurable zinc deficiency without additional dietary risk factors.

The most clinically relevant context for heterozygotes is a high-phytate diet (heavy in unfermented wholegrains, legumes, maize-based staples) combined with low animal-protein intake, where the combination of reduced transport capacity and poor zinc bioavailability could produce marginal zinc status.

CC Reduced Transport Decreased

Val372 homozygote — reduced ZIP4 surface expression and lower zinc absorption capacity; West African-ancestry genotype

Engelken et al. (2014) demonstrated in HeLa cell experiments that Val372-ZIP4 has significantly reduced surface protein expression, lower basal intracellular zinc levels, and reduced maximum zinc uptake compared to Leu372-ZIP4. The reduction is not total — Val372-ZIP4 still functions as a zinc transporter — but it operates at a lower efficiency ceiling. Because the intestinal ZIP4 is the primary route for zinc entry into the body (all dietary zinc must pass through it), even a moderate reduction in ZIP4 surface expression can meaningfully affect total daily zinc absorption.

The Val372/Val372 genotype is the population-normal for West Africans and their descendants. It was positively selected, likely because reduced zinc availability to intracellular pathogens confers survival advantages in high-pathogen-burden environments. The same zinc economy that may limit pathogen replication also creates a narrower dietary margin — particularly on phytate-heavy staple diets where bioavailability is already low.

In modern dietary contexts, the risk translates to: any dietary pattern that combines reduced ZIP4 efficiency with low animal-source protein and high phytate content creates the conditions for functional zinc inadequacy. This is clinically relevant for CC individuals eating traditional plant-based staple diets or with malabsorptive gut conditions.

Serum zinc (normal: 70–110 µg/dL) is the most accessible clinical indicator of zinc status, though it is insensitive to mild deficiency. Alkaline phosphatase activity is a complementary zinc-dependent biomarker; low-normal ALP in the context of this genotype supports marginal zinc status. A clinical dietitian can quantify dietary zinc intake against the genotype-specific absorption efficiency.