rs1801198 — TCN2 Pro259Arg (C776G)

TCN2 Pro259Arg — Your B12 Delivery System

Vitamin B12 travels through your bloodstream bound to two different proteins. About 75-80% binds to haptocorrin¹¹ haptocorrin
A B12-binding protein that carries most circulating B12 but cannot deliver it to cells; it is metabolically inert, which is metabolically inert. The remaining 20-25% binds to transcobalamin II²² transcobalamin II
The only B12 transport protein that can deliver the vitamin into cells via the transcobalamin receptor (CD320) on cell surfaces (encoded by the TCN2 gene), forming holotranscobalamin³³ holotranscobalamin
Also called "active B12" or holoTC, this is the fraction of circulating B12 that is actually available for cellular uptake (holoTC) -- the only form of B12 that can actually enter your cells. This makes holoTC a far better marker of functional B12 status than total serum B12.

The TCN2 Pro259Arg variant (rs1801198, c.776C>G) changes a proline to an arginine at position 259 of the transcobalamin protein. This single amino acid swap alters the protein's ability to bind and deliver B12, resulting in measurably lower holoTC levels in carriers of the G allele -- even when total serum B12 appears normal.

The Mechanism

Transcobalamin II is a 43 kDa protein that binds one molecule of cobalamin (B12) and delivers it to cells via the CD320 receptor⁴⁴ CD320 receptor
Also called the transcobalamin receptor (TCblR), expressed on virtually all cell surfaces. The crystal structure⁵⁵ crystal structure
Wuerges et al. solved the structure of human transcobalamin bound to cobalamin, revealing a two-domain architecture with B12 buried at the domain interface of human transcobalamin reveals a two-domain architecture with cobalamin buried at the interface between an N-terminal barrel and a smaller C-terminal domain. Position 259 lies in a region that influences the protein's secondary structure and its affinity for B12. The arginine substitution (G allele) disrupts this region, reducing the proportion of transcobalamin that successfully binds B12.

The consequence is straightforward: less B12 gets loaded onto transcobalamin, so less holoTC circulates, and less B12 reaches your cells. Total serum B12 may look perfectly normal because the haptocorrin-bound fraction (which is metabolically useless) is unaffected. This is why standard B12 blood tests can be misleading for carriers of this variant.

The Evidence

The landmark study by Miller et al.⁶⁶ landmark study by Miller et al.
Miller JW et al. Transcobalamin II 775G>C polymorphism and indices of vitamin B12 status in healthy older adults. Blood, 2002 examined 128 healthy older adults and found that Arg/Arg homozygotes (GG) had significantly lower holoTC (p = 0.006) and higher methylmalonic acid⁷⁷ methylmalonic acid
MMA is a metabolic byproduct that accumulates when cellular B12 is insufficient; elevated MMA is a sensitive functional marker of B12 deficiency (MMA) concentrations (p = 0.02) compared to Pro/Pro homozygotes, despite similar total B12 levels.

A comprehensive meta-analysis of 34 studies⁸⁸ meta-analysis of 34 studies
Oussalah A et al. Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases. Am J Clin Nutr, 2017 confirmed that GG carriers have significantly lower holoTC (SMD -0.445, 95% CI -0.673 to -0.217, p < 0.001) and higher homocysteine in European-descent populations (SMD 0.070, 95% CI 0.020-0.120, p = 0.01). The meta-analysis found no significant association with congenital abnormalities, cancer, or Alzheimer disease.

Stanislawska-Sachadyn et al.⁹⁹ Stanislawska-Sachadyn et al.
Stanislawska-Sachadyn A et al. The transcobalamin 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B12 status. Eur J Clin Nutr, 2010 studied 613 men and found that the homocysteine-raising effect of the GG genotype is most pronounced when B12 status is already low, creating a gene-nutrient interaction where inadequate B12 intake amplifies the genetic effect.

A particularly striking finding came from a study of elderly adults¹⁰¹⁰ study of elderly adults
Ratan SK et al. Transcobalamin 776C>G polymorphism is associated with peripheral neuropathy in elderly individuals with high folate intake. Am J Clin Nutr, 2016: GG carriers had roughly 3-fold higher odds of peripheral neuropathy, and when combined with high folate intake (>800 mcg/day), the risk jumped to OR 6.9. This suggests that excess folic acid may mask B12 deficiency symptoms while neurological damage progresses -- a concern particularly relevant for GG carriers.

Practical Implications

The key takeaway is that standard total serum B12 tests may not reflect your actual cellular B12 status if you carry the G allele. Request holotranscobalamin (holoTC) or methylmalonic acid (MMA) testing instead, as these directly measure the B12 that reaches your cells.

For GG carriers, choosing bioavailable forms of B12 (methylcobalamin or hydroxocobalamin rather than cyanocobalamin) may improve cellular delivery. Adequate B12 intake is especially important because the homocysteine-raising effect becomes significant when B12 status drops.

Be cautious with high-dose folic acid supplementation if you carry this variant. Excess folate can correct the anemia of B12 deficiency while allowing neurological damage to progress silently. If you also carry MTHFR variants, use methylfolate rather than folic acid, and ensure B12 status is adequate first.

Interactions

TCN2 Pro259Arg sits at the intersection of the one-carbon metabolism pathway, where B12 and folate work together. Methionine synthase (MTR, rs1805087) uses B12 as a cofactor to convert homocysteine to methionine, while methionine synthase reductase (MTRR, rs1801394) regenerates the active form of the enzyme. If TCN2 reduces B12 delivery to cells, these downstream enzymes have less cofactor to work with.

The combination of TCN2 GG with MTHFR C677T variants (rs1801133) is of particular interest: MTHFR variants impair folate metabolism while TCN2 variants impair B12 delivery, creating a double hit on the methylation cycle. Both homocysteine recycling and DNA methylation could be compromised. Individuals carrying risk variants in both genes may benefit most from combined methylfolate plus methylcobalamin supplementation and regular homocysteine monitoring.

MTRR A66G (rs1801394) variants may compound the effect of TCN2 by further reducing the efficiency of B12-dependent methionine synthase regeneration, potentially amplifying homocysteine elevation in carriers of both variants.