MTRR A66G: rs1801394 and Vitamin B12 Recycling

MTRR A66G, also called rs1801394, is a common genetic variant that helps keep a vitamin B12-dependent enzyme working. That enzyme, methionine synthase, converts homocysteine back into methionine. MTRR helps reactivate it after it becomes temporarily inactive, allowing the reaction to continue [R].

This makes MTRR an important connection between vitamin B12, folate metabolism, and homocysteine recycling. The A66G variant changes one amino acid in the MTRR protein, and laboratory experiments have identified differences in how efficiently the resulting forms reactivate methionine synthase [R].

You can explore rs1801394 in the free GenesUnveiled Methylation Panel.

Quick Answer: What Does MTRR A66G Mean?

MTRR A66G changes the amino acid at position 22 of methionine synthase reductase:

• A encodes isoleucine, abbreviated Ile or I.

• G encodes methionine, abbreviated Met or M.

The variant is therefore also called Ile22Met or I22M [R].

Its clearest functional finding concerns the efficiency of enzyme reactivation.

What Does the MTRR Gene Do?

The MTRR gene produces methionine synthase reductase. Its name is similar to methionine synthase, but the two enzymes have different jobs.

Gene	Enzyme’s role
MTR	Produces methionine synthase, which converts homocysteine into methionine.
MTRR	Produces the enzyme that helps reactivate methionine synthase when it becomes inactive.

Methionine synthase depends on a vitamin B12-derived cofactor. During its normal operation, this cofactor can become oxidized, temporarily interrupting the process. MTRR supplies the reducing power needed for reactivation [R]. This is the basis of the phrase “B12 recycling” in discussions of MTRR. It refers to restoring the working state of enzyme-bound B12 within this reaction, rather than recycling all the vitamin B12 in your body.

MTRR A66G: What Did Laboratory Research Find?

A 2002 study compared common forms of methionine synthase reductase. Researchers found that the Met22/Ser175 form required approximately three to four times the ratio of reductase to methionine synthase to achieve maximal activation compared with the Ile22/Ser175 form. The maximum activity achieved was nevertheless the same [R].

This experiment supports a difference in how efficiently the proteins interact under certain conditions. It does not establish that GG individuals have less methylation or need four times as much B12.

AA, AG, and GG: What Do Your Genotypes Mean?

Genotype	Protein forms at position 22	Interpretation
AA	Ile/Ile	Two copies encoding isoleucine.
AG	Ile/Met	One copy encoding each form.
GG	Met/Met	Two copies encoding the Met22 form investigated in functional experiments.

Does the G Allele Always Mean Higher Homocysteine?

Human studies show a more complicated picture.

A 2001 study of 601 Northern Irish men aged 30–49 found that AA, rather than GG, was associated with moderately higher homocysteine.

AA participants had 1.59 times the odds of being in the upper half of the homocysteine distribution [R].

How Vitamin Status Changes the Picture

A 2014 study examined MTRR alongside vitamin B12 and riboflavin status.

Among participants in the lowest B12 quartile—273 pmol/L or below—G-allele carriers had approximately 6.6% higher homocysteine than AA participants when riboflavin status was marginal or optimal. The same difference was not observed in the riboflavin-deficient group [R].

Together, the studies suggest that the relationship between rs1801394 and homocysteine depends partly on nutritional and biological context. A genotype cannot substitute for measuring the biomarker itself.

How MTRR Connects With MTHFR

MTHFR and MTRR contribute to different steps within connected pathways.

MTHFR helps supply the folate form used in homocysteine remethylation. MTRR helps keep the B12-dependent methionine synthase enzyme active.

A study of 362 women aged 20–30 investigated both genes alongside folate and B12 status. Some combinations involving MTHFR C677T and MTRR A66G were associated with higher homocysteine, supporting the importance of considering this connection [R].

For the folate side of this connection, read our MTHFR rs1801133 explanation.

Does MTRR A66G Mean You Need B12 Supplements?

The genotype alone cannot establish a B12 deficiency or determine a supplement dose.

The research concerns enzyme behavior and associations with biomarkers under particular conditions. It does not provide a validated supplement prescription for AA, AG, or GG. If you have concerns about B12 status or homocysteine, the useful next step is an assessment based on your diet, health history, and appropriate laboratory testing.

MTRR A66G is also different from rare disease-causing MTRR variants associated with cblE-type homocystinuria, an inherited metabolic disorder. A common A66G result does not diagnose that condition [R].

Explore Your MTRR Result in the Free Methylation Panel

MTRR adds an important piece to methylation-related genetics: keeping a B12-dependent reaction working after its enzyme becomes temporarily inactive. Your rs1801394 result helps you explore that mechanism alongside other selected markers.

Visit the free Methylation Panel to explore MTRR alongside MTHFR, MTR, TCN2, COMT, and MTHFD1. You can analyze your existing raw DNA file in your browser to see which markers are available.