Is CUBN rs1801222 associated with circulating vitamin B12 levels?

Clinical evidence and genetic associations

• Genome-wide association studies (GWAS) involving over 45,000 individuals establish a highly significant link between the CUBN rs1801222 (p.S253F) missense variant and circulating vitamin B12 levels.
• The G (Ser253) allele correlates with higher circulating cobalamin, whereas the A (Phe253) allele is associated with lower baseline levels, representing a key risk locus for deficiency.
• This genetic influence is highly pronounced in pharmacogenetic contexts; carriers of the risk allele exhibit a dose-dependent increase in B12 deficiency during metformin therapy.

Mechanistic explanations

• The CUBN gene encodes cubilin, the essential ligand-binding component of the apical Cubam receptor complex in the terminal ileum.
• Dietary vitamin B12 binds gastric intrinsic factor (IF), forming an IF-B12 complex that is recognized by CUB domains 5–8 of cubilin in a calcium-dependent manner.
• Because cubilin lacks a transmembrane domain, it pairs with the transmembrane protein amnionless (AMN). AMN recruits clathrin adaptors (such as Dab2 or ARH) to initiate clathrin-dependent endocytosis. Inside the enterocyte, cobalamin is freed and exported basolaterally into the bloodstream.
• The rs1801222 (p.S253F) polymorphism alters cubilin's protein structure, reducing its physiological absorption efficiency. Extreme genetic loss-of-function in CUBN causes severe malabsorption (Imerslund-Gräsbeck syndrome), underscoring the critical nature of this pathway.

Bottom line

• The CUBN rs1801222 variant directly alters cubilin's structural integrity, reducing its ability to endocytose the ileal intrinsic factor-B12 complex and leading to lower circulating vitamin B12 levels.