MTRR Gene Variant rs1801394: Health Risks Explained

Last reviewed: May 12, 2026 Last updated: May 12, 2026

Written by: Jay Hastings , CEO of PlexusDx

Jay Hastings is the CEO of PlexusDx, a precision health company focused on genetic testing, blood biomarker insights, and personalized wellness recommendations. He has more than 20 years of experience across healthcare innovation, genomics, laboratory operations, healthcare investing, and strategic finance. His work has included scaling healthcare startups, leading CLIA lab integrations, and helping expand consumer access to precision health tools.

Medically reviewed by: Jayden Lee, PharmD, EMBA

Jayden Lee, PharmD, EMBA, is the PlexusDx Medical Science Liaison with a PharmD and MBA specializing in pharmacogenomics and clinical product development, with a proven ability to bridge the gap between genomic research and practical patient outcomes. Dr. Lee has more than 10 years of professional experience in clinical pharmacy, academia, and research.

This article is part of the PlexusDx Education Hub — your resource for evidence-based guidance on methylation & mthfr. Browse all Methylation & MTHFR education

The MTRR gene variant rs1801394 sits at a quiet but important junction of your methylation machinery. It is common — a large share of the population carries at least one copy — and it influences how efficiently your body recycles vitamin B12 to keep homocysteine in check.

This article explains what MTRR does, what the rs1801394 (A66G) variant changes, and which health associations the research actually supports — without overstating what a single genotype means for you.

What the MTRR gene does

MTRR stands for methionine synthase reductase. Its job is to reactivate an enzyme called methionine synthase (encoded by the MTR gene), which converts homocysteine back into methionine using a vitamin B12-dependent step. Over time, the B12 cofactor in that reaction becomes oxidized and inactive; MTRR restores it so the cycle can continue.

Without efficient MTRR activity, methionine synthase stalls, homocysteine can accumulate, and the supply of methyl groups the body uses for DNA, neurotransmitters, and detoxification can tighten. MTRR is therefore a maintenance gene for the entire methylation cycle.

The rs1801394 (A66G) variant

rs1801394 is a single-nucleotide change (A66G) that swaps isoleucine for methionine at position 22 of the MTRR protein. The G (variant) allele is associated with somewhat reduced enzyme efficiency, meaning the B12 cofactor is reactivated a little less readily.

On its own, the effect of rs1801394 is modest. Its significance grows when it is combined with other methylation variants — particularly MTHFR C677T and MTR A2756G — and when vitamin B12 or folate status is low. Genetics and nutrition interact here rather than acting in isolation.

Health associations the research supports

The most consistent association is with homocysteine, an amino acid that rises when the methylation cycle runs inefficiently. Elevated homocysteine has itself been studied as a marker linked to cardiovascular and vascular health, though it is a marker, not a diagnosis.

Research has also examined rs1801394 in the context of neural tube defect risk in pregnancy (where folate and B12 status are central), and, in some studies, maternal risk factors and cognitive aging. Findings are mixed and often depend on B-vitamin status, which is why the variant is best understood as one modifiable-context factor rather than a fixed risk.

How MTRR works with MTHFR and B12

Methylation is a relay, not a solo act. MTHFR generates the active folate form; MTR uses it plus B12 to remethylate homocysteine; and MTRR keeps MTR's B12 cofactor functional. A variant in any one of these can be partly buffered if the others and their nutrient cofactors are working well.

This is why providers often look at MTRR alongside MTHFR, MTR, homocysteine levels, and vitamin B12 and folate status together. The genotype sets a tendency; nutrient status and the rest of the pathway determine how that tendency plays out.

What genetic testing can tell you

A genetic test can identify whether you carry the rs1801394 variant and place it in the context of your broader methylation pathway. It cannot diagnose a disease, and it does not tell you that homocysteine is elevated — that requires a blood test.

The PlexusDx Precision Peptide Genetic Test analyzes 14 pathways, 49 peptides, 150+ genetic insights, including methylation-related variants such as those in MTRR and MTHFR. It provides pathway-level context about your biology, not a treatment plan, and it is not a pharmacogenomic test. As the governing principle goes: PlexusDx tells you about your biology; it does not tell you what to put in your body.

What to do with the information

If you carry rs1801394, the practical next step is a conversation with a qualified provider about whether checking homocysteine, vitamin B12, and folate makes sense for you. Because the variant's impact depends heavily on nutrient status, that status is often the most actionable lever.

Genetics is a guide, not a guarantee. Carrying the G allele does not mean your methylation is impaired — it means the pathway is worth understanding in the context of your labs, diet, and health history.

Frequently Asked Questions

What does the MTRR rs1801394 variant do?

The rs1801394 (A66G) variant modestly reduces the efficiency of methionine synthase reductase, the enzyme that reactivates the vitamin B12 cofactor needed to recycle homocysteine into methionine. The effect is small alone but can matter more when combined with other methylation variants or low B12 and folate.

Is rs1801394 a dangerous mutation?

No. rs1801394 is a common variant, not a disease-causing mutation. It shifts a metabolic tendency rather than guaranteeing any outcome. Its relevance depends on your overall methylation pathway, vitamin B12 and folate status, and homocysteine levels, which is why context matters far more than the genotype alone.

Does rs1801394 affect homocysteine?

It can contribute. Because MTRR keeps the homocysteine-recycling step running efficiently, reduced MTRR activity is associated with higher homocysteine in some people, especially when B12 or folate is low. Homocysteine is a blood marker, so only a lab test can show your actual level.

Can genetic testing diagnose a health condition from rs1801394?

No. Genetic testing identifies the variant and places it in your methylation pathway, but it does not diagnose, treat, or manage any condition. Diagnosis relies on clinical evaluation and lab work ordered by a qualified healthcare provider, who can interpret the variant alongside your labs and history.

Want to see where rs1801394 fits in your own methylation pathway? Explore the Precision Peptide Genetic Test to understand how your DNA shapes these biological pathways — context you can review with your healthcare provider.

Disclaimer: The Precision Peptide Genetic Test analyzes how your genes influence peptide-related biological pathways. It does not recommend, prescribe, or determine which peptides you should use, and it does not diagnose, treat, cure, or prevent any disease. Consult a qualified healthcare provider before beginning any peptide protocol.

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Medical and Editorial Standards

Medical review process: This article was reviewed for medical accuracy, scientific clarity, evidence alignment, and appropriate discussion of genetics, medications, supplements, biomarkers, and health-related claims.

Sources and evidence: PlexusDx educational content is developed using peer-reviewed research, clinical literature, reputable medical references, and, where applicable, public health or regulatory guidance. References are included at the end of the article when scientific, medical, or health-related claims are discussed.

Commercial transparency: PlexusDx offers genetic testing, blood biomarker testing, personalized supplement recommendations, and related precision wellness services. Product mentions are intended to help readers understand available options and should not be interpreted as medical advice.

Important disclaimer: PlexusDx educational content is for informational purposes only and should not be used as a substitute for professional medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider before making decisions about medications, supplements, genetic testing, lab testing, or health-related care.