MTHFR rs1801133: What Your Genotype Means
The rs1801133 single nucleotide polymorphism, commonly known as 677C>T or Ala222Val, is a frequent missense variant in the MTHFR gene that encodes a thermolabile enzyme with reduced catalytic activity. Individuals carrying the variant allele, particularly homozygotes, often exhibit mildly elevated plasma homocysteine levels, especially when dietary folate or B-vitamin status is low. Despite widespread interest, major professional genetics societies advise against routine clinical screening for this polymorphism in evaluating cardiovascular disease or thrombophilia.
What each genotype means
| Genotype | What the research suggests | Reading |
|---|---|---|
| CC | Carriers of the CC genotype possess two copies of the ancestral cytosine allele and display baseline, wild-type MTHFR enzyme activity. These individuals typically maintain expected folate cycle dynamics and standard homocysteine clearance under normal dietary intake. They face no genetically increased thermolability or elevated homocysteine driven by this specific locus. | Favorable |
| CT | Individuals with the CT heterozygous genotype carry one copy of the thermolabile T variant and maintain approximately 65% of typical MTHFR enzyme activity. This intermediate reduction is rarely clinically meaningful on its own when dietary intake of folate and related B vitamins is adequate. In population research, this common genotype is treated as a benign carrier state that does not elevate disease risk independently. | Informational |
| TT | Homozygous TT individuals carry two copies of the variant, producing an enzyme with significantly higher thermolability and approximately 30% to 50% of standard catalytic activity. This reduced activity can lead to higher baseline plasma homocysteine levels, especially when dietary folate or riboflavin levels are low. While associated statistically with metabolic shifts, major genetics guidelines do not consider this genotype a standalone diagnostic disease marker. | Higher attention |
What Is rs1801133 and Where Is It Located?
The genetic variant rs1801133 represents a single base substitution located within the methylenetetrahydrofolate reductase (MTHFR) gene on human chromosome 1. In standard molecular nomenclature, it is described as c.665C>T (transcript NM_005957.5) and historically as 677C>T. This change swaps a cytosine for a thymine, leading to an amino acid replacement of alanine with valine at position 222 (p.Ala222Val). Because alanine is replaced in the catalytic domain, the resulting enzyme exhibits thermolability—meaning it loses catalytic stability and degrades more rapidly at normal body temperatures. Documented in genomic repositories such as dbSNP and ClinVar, rs1801133 is one of the most extensively researched single nucleotide polymorphisms in human biochemical genetics.
The Biological Role of the MTHFR Enzyme
The MTHFR gene codes for an essential enzyme that catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate. This biochemical step is vital to the cellular folate and methionine cycles. Five-methyltetrahydrofolate serves as the primary methyl donor for remethylating homocysteine into methionine, an essential amino acid required for cellular protein synthesis and the production of S-adenosylmethionine (SAMe). Because SAMe is the principal methyl donor for DNA methylation and cellular biochemical reactions, proper MTHFR function helps maintain healthy epigenetic regulation and prevents the cellular accumulation of total plasma homocysteine, a biomarker closely monitored in metabolic health research.
Scientific Evidence and Health Associations
Biochemically, rs1801133 is well established: the T allele reliably reduces enzyme efficiency, with homozygous TT carriers displaying roughly 30% to 50% of typical wild-type activity, often coinciding with elevated plasma homocysteine when folate intake is low. In clinical epidemiology, the variant has been evaluated across thousands of studies for possible links to deep vein thrombosis, cardiovascular disease, recurrent pregnancy loss, and methotrexate toxicity. However, large meta-analyses and mendelian randomization trials show conflicting results regarding whether rs1801133 causally drives clinical cardiovascular events. Pharmacogenomic databases such as PharmGKB annotate rs1801133 for its moderate association with altered methotrexate tolerance, but major professional bodies like the American College of Medical Genetics and Genomics (ACMG) emphasize that its predictive value for common multifactorial conditions is minimal.
Global Ancestry and Population Frequencies
The rs1801133 variant is common worldwide, though its allele distribution varies dramatically among ancestral populations. Large population datasets, such as the Genome Aggregation Database (gnomAD), indicate an overall global allele frequency for the alternative T allele of roughly 30%. The T allele occurs at its lowest frequencies in individuals of African ancestry, where the minor allele frequency is approximately 10% and homozygous TT individuals comprise only about 1% to 6% of the population. Conversely, the T allele reaches frequencies between 30% and 35% in European populations, and up to 45% to 50% in East Asian and Hispanic cohorts, where more than 20% to 25% of individuals carry two copies of the variant.
Clinical Guidelines and Interpreting Your Results
Learning that you carry one or two copies of the rs1801133 T allele does not equate to a diagnosis of clinical illness or severe genetic deficiency. Practice guidelines published by the American College of Medical Genetics and Genomics explicitly advise against ordering routine MTHFR polymorphism testing during clinical evaluations for recurrent pregnancy loss or thrombophilia, noting that the presence of the variant lacks actionable clinical utility. If individuals have concerns regarding homocysteine metabolism or nutritional status, standard clinical blood tests measuring serum folate, vitamin B12, and plasma homocysteine provide far more direct medical insight. Readers taking medications influenced by folate metabolism, such as methotrexate, should always consult their physician or pharmacist prior to making any medical or supplement adjustments.
How common is this variant?
The minor T allele frequency ranges from approximately 10% in populations of African descent to 30–35% in Europeans, reaching 45–50% in Hispanic and East Asian populations where over 20% of individuals are TT homozygotes.
Frequently asked questions
Does having the MTHFR rs1801133 TT genotype mean I have MTHFR deficiency?
No, having the common rs1801133 TT genotype does not mean you have severe clinical MTHFR deficiency. Severe MTHFR deficiency is an extremely rare metabolic condition caused by distinct, severe mutations that nearly eliminate enzyme activity. The rs1801133 variant is a common polymorphism found in up to a quarter of certain healthy populations and merely causes mild enzyme inefficiency.
Should I get tested for rs1801133 if I have blood clots or heart issues?
Professional medical organizations, such as the American College of Medical Genetics and Genomics (ACMG), advise against routine genetic testing for MTHFR variants in cardiovascular and clotting workups. Clinical trials have found that lowering homocysteine through supplements does not meaningfully reduce heart attacks or thrombotic events. Direct blood tests of homocysteine levels offer more clinical value than this genetic test.
Can diet influence how the rs1801133 variant affects the body?
Yes, nutritional status plays a substantial role in modulating the biochemical impact of rs1801133. The enzyme thermolability and elevated homocysteine associated with the TT genotype are observed predominantly when folate, vitamin B12, and riboflavin levels are suboptimal. Maintaining adequate intake of dietary folate helps support standard enzyme function regardless of genotype.
How does rs1801133 affect medications like methotrexate?
Because methotrexate interferes with cellular folate pathways, researchers cataloged in pharmacogenomic resources like PharmGKB have observed altered drug tolerance or higher toxicity risks in some rs1801133 variant carriers. However, dosing strategies must never be adjusted based on a consumer genetic test alone. Always speak with your prescribing clinician or clinical pharmacist before altering any medical treatment.
Sources & further reading
Educational information only, last refreshed 9/8/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Functional missense variant affecting methylene tetrahydrofolate reductase activity, altering homocysteine clearance pathways and folate-dependent cardiovascular susceptibility.
Functional intronic/regulatory variant in MTHFR linked to altered enzyme expression and plasma folate/homocysteine homeostasis.
Located within the MTHFR locus, this variant has been examined in association studies concerning folate metabolism and homocysteine regulation.
MTHFR missense variant (c.1793G>A, p.Arg594Gln) commonly evaluated alongside canonical variants for folate metabolism and hyperhomocysteinemia predisposition.
The MTHFR c.1298A>C (p.Glu429Ala) missense variant causes a modest reduction in enzyme activity, but major clinical consensus guidelines and recent GWAS indicate it has no independent clinical significance for thrombophilia or folate biomarker deficiency in isolation.
Nonsense variant in MTHFR (p.Gln387Ter) causing severe homocystinuria and MTHFR deficiency in recessive states.