rs4588 — GC Thr436Lys

Vitamin D Binding Protein — The Carrier That Shapes Your D Levels

The GC gene encodes vitamin D binding protein (VDBP/DBP)¹¹ vitamin D binding protein (VDBP/DBP)
A 58-kDa glycoprotein produced mainly by the liver, also called group-specific component (Gc). It carries 85-90% of circulating 25(OH)D and 85% of 1,25(OH)₂D in the bloodstream, the main transport protein for vitamin D metabolites in the blood. Nearly all circulating 25-hydroxyvitamin D — the form your doctor measures — travels bound to VDBP. A single nucleotide change at rs4588 swaps a threonine for a lysine at position 436 of the protein, defining the boundary between the Gc1 and Gc2 isoforms. This amino acid substitution removes a key O-glycosylation²² O-glycosylation
A post-translational modification where a sugar (N-acetylgalactosamine) attaches to the threonine at position 436. The Gc2 isoform (lysine) cannot be glycosylated at this site, altering protein stability and binding properties site, lowering both the protein's binding affinity for vitamin D metabolites and its overall serum concentration.

The Mechanism

VDBP exists in three major isoforms defined by two SNPs — rs4588 and rs7041³³ rs7041
The other key GC variant (Asp432Glu), which together with rs4588 defines the Gc1f, Gc1s, and Gc2 haplotypes. The rs4588 T allele (Lys436) creates the Gc2 isoform, while the G allele (Thr436) is shared by both Gc1f and Gc1s isoforms. The Gc2 protein has lower affinity for 25(OH)D and 1,25(OH)₂D⁴⁴ 1,25(OH)₂D
The active hormonal form of vitamin D (calcitriol), produced in the kidneys from 25(OH)D compared to the Gc1 variants. Together, rs4588 and rs7041 explain over 50% of the variance in circulating VDBP concentration — a remarkably large genetic effect for any serum protein.

Because VDBP carries most circulating vitamin D, people with the Gc2 isoform (TT homozygotes) have measurably lower total 25(OH)D on standard blood tests. However, the lower binding affinity simultaneously means that a greater proportion of their vitamin D is in the free or bioavailable⁵⁵ bioavailable
The fraction of 25(OH)D not bound to VDBP — consisting of the truly free fraction plus the loosely albumin-bound fraction. This is the portion that can enter cells and exert biological effects form. This creates an important paradox: a blood test showing "low" total 25(OH)D may not reflect true vitamin D insufficiency in someone with the Gc2 genotype.

The Evidence

The GC locus was identified as the strongest genetic determinant of circulating 25(OH)D in the first large GWAS studies⁶⁶ GWAS studies
Wang TJ et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010 of vitamin D levels. The expanded SUNLIGHT consortium analysis⁷⁷ expanded SUNLIGHT consortium analysis
Jiang X et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun, 2018 of 79,366 Europeans confirmed rs4588 as likely causal at this locus (per-allele beta = -0.11 standard deviations for 25(OH)D, P = 1.5 x 10⁻¹³). The most recent mega-GWAS⁸⁸ mega-GWAS
Revez JA et al. Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat Commun, 2020 of 417,580 individuals identified 143 loci affecting vitamin D levels, yet GC remained the single strongest signal in the genome.

A landmark New England Journal of Medicine study⁹⁹ New England Journal of Medicine study
Powe CE et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med, 2013 demonstrated the clinical relevance of VDBP genotype. Black Americans had substantially lower total 25(OH)D (15.6 vs 25.8 ng/mL) and lower VDBP levels than White Americans, yet their bioavailable 25(OH)D concentrations were similar (2.9 vs 3.1 ng/mL, P = 0.71) and their bone mineral density was higher. The difference was largely explained by the higher frequency of Gc1f alleles (lower VDBP, lower total D, but adequate free D) in populations of African descent.

Supplementation studies show that response to vitamin D varies by GC genotype¹⁰¹⁰ response to vitamin D varies by GC genotype
Al-Daghri NM et al. Efficacy of vitamin D supplementation according to vitamin D-binding protein polymorphisms. Nutrition, 2019. Carriers of the rs4588 TT genotype may show a smaller rise in total 25(OH)D after standard supplementation, though the clinical significance of this — given the bioavailability paradox — remains debated.

Practical Implications

The key takeaway for carriers of the T allele is that standard 25(OH)D blood tests may underestimate your functional vitamin D status. A "low" reading does not necessarily mean you are deficient in the biologically active form. If your total 25(OH)D is borderline low (20-30 ng/mL) and you have no symptoms of deficiency (fatigue, bone pain, muscle weakness), your bioavailable vitamin D may be perfectly adequate.

For TT homozygotes who do show true deficiency with symptoms or very low levels (below 20 ng/mL), vitamin D3 (cholecalciferol) supplementation remains effective — you may simply need a higher dose or longer duration to reach the same total 25(OH)D target on blood tests. Taking vitamin D with a fat-containing meal improves absorption regardless of genotype.

Interactions

rs4588 is in strong linkage disequilibrium with rs7041 (Asp432Glu), the other major GC variant. Together they define the three classical VDBP isoforms: Gc1f (rs7041-T + rs4588-G), Gc1s (rs7041-G + rs4588-G), and Gc2 (rs7041-T + rs4588-T). The Gc2/2 diplotype (homozygous for both variant alleles) has the lowest VDBP levels and the greatest reduction in total 25(OH)D, while Gc1f/1f has the highest VDBP concentration.

Variants in other vitamin D pathway genes — CYP2R1 (hepatic 25-hydroxylation), DHCR7/NADSYN1 (skin synthesis), and CYP24A1 (degradation) — can compound the effect of GC variants. Someone who carries both a low-transport GC genotype and impaired synthesis or hydroxylation variants may be at genuinely higher risk of functional vitamin D insufficiency.