rs602662 — FUT2 Gly258Ser

FUT2 Gly258Ser — A Second Handle on Your Vitamin B12 Levels

Your circulating vitamin B12 is not simply a readout of how much B12 you eat — it is actively shaped by the proteins that carry B12 in your blood and determine how quickly it is cleared from circulation. The FUT2 gene encodes alpha-(1,2)-fucosyltransferase 2¹¹ alpha-(1,2)-fucosyltransferase 2
An enzyme that adds fucose sugar residues to glycan chains on cell surfaces and on secreted proteins, creating the H blood group antigen on mucosal surfaces and modifying the glycosylation of carrier proteins like haptocorrin, an enzyme that influences B12 metabolism through a specific post-translational modification of haptocorrin — the protein that binds most of the B12 in your blood. The Gly258Ser variant (rs602662) changes a glycine to a serine at amino acid position 258 of the FUT2 protein. People with the G allele (Gly258) carry a form of FUT2 that more actively fucosylates haptocorrin, leading to lower measured serum B12. People with two A alleles (Ser258) have altered enzyme activity, less fucosylation of haptocorrin, and paradoxically higher circulating B12 measurements. This variant is in strong linkage disequilibrium²² linkage disequilibrium
When two SNPs are inherited together so frequently that knowing one predicts the other — in this case r² = 0.76-0.92 in Europeans with rs601338 (the W143X nonsense mutation that determines classical secretor status), but represents an independent missense change with its own protein-level consequences on enzymatic activity.

The Mechanism

FUT2 fucosylates haptocorrin³³ haptocorrin
Also called transcobalamin I or R-binder — a heavily glycosylated protein synthesized mainly by salivary glands and gastric mucosa that binds B12 in the gut to protect it from acid degradation, then releases it in the small intestine. In the bloodstream, haptocorrin carries approximately 70-80% of total serum B12, adding fucose residues to its complex glycan chains. This fucosylation affects how haptocorrin is recognized and cleared by the liver. The asialoglycoprotein receptor⁴⁴ asialoglycoprotein receptor
A lectin receptor on hepatocytes that preferentially binds and internalizes glycoproteins bearing exposed galactose or N-acetylgalactosamine residues — residues that become exposed when the terminal sialic acid is removed. Fucosylation competes with sialylation on these glycan positions, altering which glycoforms predominate (ASGR) on liver cells is responsible for clearing haptocorrin from the bloodstream. The degree of fucosylation alters the rate of this hepatic clearance. In carriers of the G allele (Gly258, higher FUT2 activity), haptocorrin is more thoroughly fucosylated, shifts toward the TCIII glycoform, and is cleared more efficiently from the blood — resulting in lower measured serum B12. In AA individuals (Ser258, lower FUT2 activity on this residue), haptocorrin retains more sialylation, resists ASGR-mediated clearance, and accumulates to higher levels in the bloodstream. Critically, Velkova et al. 2017⁵⁵ Velkova et al. 2017
Velkova A et al. The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation. Hum Mol Genet, 2017 demonstrated that these FUT2 variants only affect holo-haptocorrin, not holo-transcobalamin⁶⁶ holo-transcobalamin
The approximately 20-30% of blood B12 bound to transcobalamin II — the only form actively taken up by cells via the TCN2 receptor. Only holoTC reflects the B12 available for cellular use; haptocorrin- bound B12 is not accessible to most cells — the biologically active fraction. This is the critical practical implication: standard serum B12 tests measure total B12 (mostly haptocorrin-bound), and GG individuals with lower total B12 may actually have normal cellular B12 availability, while standard tests can give an artificially low result. Conversely, AA individuals with higher total B12 measurements may have perfectly normal cellular B12 availability.

The Evidence

Two independent GWAS studies identified rs602662 as a top hit for plasma vitamin B12. Tanaka et al. 2009⁷⁷ Tanaka et al. 2009
Tanaka T et al. Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet, 2009 analyzed 3,622 participants in three Italian cohorts and found rs602662 to be the single strongest genetic association with vitamin B12 (p = 2.83 x 10^-20). The combined analysis by Hazra et al. 2008⁸⁸ Hazra et al. 2008
Hazra A et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet, 2008 in 2,717 women identified the FUT2 locus (lead SNP rs492602, in strong LD with rs602662) at p = 5.36 × 10⁻¹⁷, with GG individuals having substantially lower B12 than the AA group. A 2024 study in kidney transplant patients Kotowski et al.⁹⁹ Kotowski et al.
Kotowski M et al. The Importance of the FUT2 rs602662 Polymorphism in the Risk of Cardiovascular Complications in Patients after Kidney Transplantation. Int J Mol Sci, 2024 found that the G allele was present in 65% of hypertensive patients versus 56% of normotensive patients — consistent with the lower B12 leading to higher homocysteine and greater cardiovascular risk. A metabolic study de Luis et al. 2022¹⁰¹⁰ de Luis et al. 2022
de Luis DA et al. Effect of the variant rs602662 of FUT2 gene on anthropometric and metabolic parameters in a Caucasian obese population. Eur Rev Med Pharmacol Sci, 2022 found that AA homozygotes had significantly lower BMI, better lipid profiles, lower fasting glucose, reduced insulin resistance, and a 72% lower metabolic syndrome risk (OR 0.28) compared to GG+GA carriers — an observation that may connect FUT2 biology to wider metabolic regulation.

Practical Implications

The key practical point for GG individuals (and to a lesser extent GA carriers) is awareness: if your standard serum B12 test comes back in the lower-normal range, your result may be influenced by your genotype rather than your dietary intake alone. Requesting a holotranscobalamin¹¹¹¹ holotranscobalamin
Also called "active B12" or holoTC — the B12 fraction bound to transcobalamin II that is available for cellular uptake. Normal range is typically above 35-50 pmol/L test instead of, or alongside, total serum B12 gives a more accurate picture of your functional B12 status. Alternatively, methylmalonic acid (MMA) — which rises specifically when cells lack functional B12 — provides a direct functional readout. For AA individuals, the opposite consideration applies: your total serum B12 may read higher than average, but this primarily reflects haptocorrin-bound B12 in circulation, not improved cellular availability. Standard B12 testing can be misleadingly reassuring if cellular deficiency is a concern.

Interactions

rs602662 is in strong linkage disequilibrium with rs601338 (W143X, the primary European secretor variant) with r² = 0.76-0.92 in Europeans. Together these variants capture FUT2 enzymatic activity from two different positions in the protein — rs601338 causes complete truncation at Trp143, while rs602662 alters activity at Gly258. The associated B12-lowering effects of both variants are mediated through the same haptocorrin glycosylation mechanism, and their effects largely overlap in European populations. For individuals of East Asian ancestry, the classical W143X non-secretor allele (rs601338) is nearly absent. A different FUT2 variant, rs1047781 (A385T, Ile129Phe), is the primary East Asian non-secretor allele. The rs602662 Gly258Ser change is correspondingly rare in East Asian populations, making this variant much less informative in that ancestry context. The downstream effect of lower B12 from GG genotypes intersects with one-carbon metabolism. Vitamin B12 is required for the methionine synthase reaction that converts homocysteine back to methionine. Chronically lower B12 can raise homocysteine, increasing cardiovascular and neurological risk. This interaction is especially relevant in individuals who also carry MTHFR variants (rs1801133 C677T or rs1801131 A1298C) that impair folate-driven remethylation — the two pathways jointly determine homocysteine levels.