rs6596473 — SLC23A1 SLC23A1 variant

Intronic variant in the intestinal and renal vitamin C transporter gene (SVCT1) associated with modestly lower plasma vitamin C levels and increased risk of aggressive periodontitis; the C allele forms part of the Crohn disease risk haplotype at the SLC23A1 locus

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SLC23A1 rs6596473 — A Third Signal in Your Vitamin C Transporter Gene

The human body cannot synthesise vitamin C. Every milligram of ascorbate11 ascorbate
The active, ionized form of ascorbic acid at physiological pH, the predominant form in blood and tissues in circulation arrived through an active transport mechanism: SVCT122 SVCT1
Sodium-dependent Vitamin C Transporter 1 — encoded by SLC23A1 on chromosome 5q23.2, expressed primarily on the apical surface of small-intestinal enterocytes and renal proximal tubule cells extracts ascorbate from ingested food in the gut and conserves it in the kidneys before it can be lost in urine. rs6596473 is an intronic variant within the SLC23A1 gene — a third independent signal at this locus alongside the well-characterised rs3397231333 rs33972313
Val264Met missense variant — the primary functional signal at SLC23A1, altering the SVCT1 protein structure and reducing both intestinal absorption and renal reabsorption efficiency (Val264Met) and rs1195064644 rs11950646
An intronic regulatory variant in SLC23A1 independently predicting plasma vitamin C levels across European cohorts (a second regulatory variant). Together these three variants map the genetic architecture of vitamin C transport at a single gene locus.

The Mechanism

rs6596473 sits within an intron of SLC23A1 at GRCh38 chromosomal position 139,374,887. Intronic variants are not silent — they can harbour splice regulatory elements55 splice regulatory elements
Intronic enhancer and silencer sequences that bind RNA-binding proteins, modulate the recognition of nearby splice sites, and alter both the efficiency and the pattern of exon inclusion in the mature mRNA, secondary promoters, or transcription factor binding sites. The molecular consequence of rs6596473 has not been characterised in published functional experiments. What the genetic data do establish is that the C allele is in strong linkage disequilibrium (D' = 0.94) with rs10063949, another intronic SLC23A1 variant, suggesting these two sites may be inherited together and tag the same regulatory effect on SVCT1 expression or function.

Unlike the missense variant rs33972313 (Val264Met), which directly alters the SVCT1 transporter protein, rs6596473 likely exerts its effect through regulatory means — influencing the quantity or splicing pattern of the SVCT1 transcript. This is consistent with the modest and somewhat variable effect sizes seen across cohorts.

The Evidence

The initial evidence for rs6596473 came from Timpson et al. 201066 Timpson et al. 2010
Genetic variation at the SLC23A1 locus is associated with circulating concentrations of L-ascorbic acid (vitamin C): evidence from 5 independent studies with >15,000 participants. Am J Clin Nutr, 2010, a staged meta-analysis beginning with the British Women's Heart and Health Study (BWHHS) discovery cohort. In that cohort, the C allele at rs6596473 (minor allele frequency 0.28) showed a nominally significant directional association with plasma vitamin C. The effect replicated directionally in EPIC-Norfolk (+1.01 µmol/L; p = 0.02), but rs6596473 was not taken forward into the three additional replication cohorts because rs33972313 emerged as the cleaner primary signal. This places the variant's vitamin C association at an emerging evidence level.

More consistent evidence comes from the de Jong et al. 2014 periodontitis study77 de Jong et al. 2014 periodontitis study
SLC23A1 polymorphism rs6596473 in the vitamin C transporter SVCT1 is associated with aggressive periodontitis. J Clin Periodontol, 2014, which found enrichment of the rare C allele in aggressive periodontitis (AgP) cases in a multi-stage European cohort study. After pooling the German case cohort (674 cases, 2,891 controls), the C allele showed a statistically significant association with AgP (OR 1.35, p = 0.005 after adjustment for smoking and sex). Aggressive periodontitis is characterised by rapid alveolar bone destruction in younger patients — a condition in which vitamin C-dependent collagen synthesis and immune cell function in gingival tissue are thought to be pathophysiologically relevant.

Additional evidence comes from Crohn disease genetics. Shaghaghi et al. 201488 Shaghaghi et al. 2014
Polymorphisms in the sodium-dependent ascorbate transporter gene SLC23A1 are associated with susceptibility to Crohn disease. Am J Clin Nutr, 2014 genotyped 162 Crohn disease patients, 149 ulcerative colitis patients, and 142 controls from the Manitoba IBD Cohort Study. The C allele at rs6596473 forms part of the CGG risk haplotype (rs6596473-C, rs33972313-G, rs10063949-G) that is carried by 65.3% of Crohn disease patients versus 43.5% of controls (P < 0.0001), in strong LD with the primary driver rs10063949 (D' = 0.94). The biological rationale is that SVCT1 is the dominant vitamin C transporter in intestinal epithelial cells — reduced SVCT1 function would impair mucosal ascorbate concentrations, weakening the antioxidant defence of the gut lining.

Practical Actions

The C allele at rs6596473 is common in European populations (MAF ~31%) but is even more frequent in East Asian (~67%) and African (~64%) populations. In Europeans, approximately 43% of people are heterozygous CG carriers and 9% are CC homozygotes. This means the majority of CC homozygotes are relatively uncommon in Europe compared to East Asia, where CC is the most common genotype.

The clinical picture is one of subtly reduced SVCT1-mediated vitamin C absorption and/or renal reabsorption. The actionable response is the same as for other SLC23A1 variants: attention to consistent dietary vitamin C intake across the day, using multiple smaller servings rather than a single large dose to work around intestinal absorption saturation, and considering a modest daily supplement if dietary intake is inconsistent.

Interactions

rs6596473 acts at the same SLC23A1 locus as the stronger primary signals rs33972313 (Val264Met) and rs11950646 (a second regulatory variant). It is in strong LD with rs10063949 (D' = 0.94), meaning these two variants are frequently co-inherited. Individuals carrying risk alleles at multiple SLC23A1 positions face compounded reductions in SVCT1-mediated transport. Variants in SLC23A2 (encoding SVCT2, responsible for tissue-level vitamin C delivery to brain, adrenals, and immune cells) act in parallel — carrying risk alleles at both loci simultaneously reduces both whole-body availability and cellular delivery of ascorbate.

Nutrient Interactions

vitamin C reduced_absorption

Genotype Interpretations

What each possible genotype means for this variant.

GG Reference Transporter Normal

Two reference copies — vitamin C transport at baseline efficiency

You carry two copies of the G reference allele at this intronic SLC23A1 position. G is the ancestral allele and the majority allele in European populations (~69% frequency). Your SVCT1 gene carries no variant at this specific regulatory site, and your plasma vitamin C levels are primarily determined by dietary intake rather than a genetic constraint at this locus.

Approximately 48% of Europeans carry this GG genotype. In East Asian and African populations, where the C allele is much more common, GG is rare (~11–13%). Your vitamin C absorption and renal conservation proceed at the reference baseline for this variant.

CG One Risk Allele Intermediate

One C allele — mildly reduced SVCT1 transport efficiency

The CG genotype at rs6596473 places one copy of the C allele at an intronic regulatory position in SLC23A1. As an additive variant, one C allele produces an intermediate reduction in SVCT1 output relative to GG. This variant is in strong LD (D' = 0.94) with rs10063949, so its biological effect likely involves the same regulatory element or haplotype block.

The periodontitis association (de Jong et al. 2014) was observed using the rare C allele across genotypes — CG and CC individuals collectively showed enrichment in aggressive periodontitis cases. Gingival tissue relies on SVCT1 for vitamin C delivery to support collagen synthesis and immune cell-mediated bone protection.

The Crohn disease CGG risk haplotype includes the C allele at rs6596473 — individuals carrying even one C allele contribute to the LD block that is enriched in Crohn disease patients, though the primary driver appears to be rs10063949.

CC Two Risk Alleles Reduced

Two C alleles — consistently lower plasma vitamin C predicted

With two copies of the C allele, both regulatory alleles at this SLC23A1 intronic site carry the variant. In the additive model consistent with this variant's inheritance pattern, CC homozygotes show the greatest predicted reduction in SVCT1 transport efficiency at this locus. The periodontitis study (de Jong et al. 2014) pooled CC and CG individuals as "C allele carriers," but the dose-response pattern — more C alleles, lower vitamin C — is consistent with both the Toronto data and the broader biology of SVCT1-mediated transport.

This variant is in strong LD (D' = 0.94) with rs10063949, meaning CC individuals are very likely also carrying the rs10063949-G allele, which is the primary driver of the Crohn disease CGG risk haplotype. The two variants likely tag the same functional regulatory element within SLC23A1's intron.

At 25.7 µmol/L average plasma vitamin C (Toronto Nutrigenomics), CC individuals are approaching the insufficiency threshold of 28 µmol/L that is associated with increased oxidative stress markers. This does not indicate deficiency in isolation, but it means dietary vitamin C adequacy is more consequential for CC individuals than for GG carriers.