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MTHFR mutations explained, frequency of C677T SNP, A1298C SNP, Supplement Interaction, MTHFR variant risks

MTHFR Gene Explained: C677T and A1298C Variants, Testing, and Solutions

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Key takeaways:
  • The MTHFR enzyme converts folate (vitamin B9) to its active form, 5-MTHF.
  • Folate is used to create methyl groups, which cells use to synthesize neurotransmitters, detoxify toxicants, methylate DNA, and maintain a healthy heart.
  • The common MTHFR C677T and A1298C variants lower enzyme function (up to ~70–80% for C677T homozygous, ~20% for A1298C homozygous), especially when folate is limited.
  • You don’t need expensive testing for MTHFR; you can check your C677T and A1298C SNPs in 23andMe, AncestryDNA, or similar raw data files.
  • Optimizing your diet and nutrient intake to align with your genetic variants may help to improve overall wellness and healthy aging.
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What is the MTHFR gene?

MTHFR is a central gene in the methylation cycle and is a limiting factor for producing methyl groups from folate (vitamin B9). Specifically, the MTHFR gene codes for an enzyme called methylenetetrahydrofolate reductase that turns folate into the active form, 5-methyltetrahydrofolate. This enzyme, along with the active form of vitamin B12 (methylcobalamin), drives an essential portion of the methylation cycle. Common genetic variants, called MTHFR C677T and A1298C, affect how the enzyme works and impact the availability of methyl groups.[ref] Genetic variants are variations in the DNA sequence that can influence the function of a gene or the protein it encodes. 

Which DNA tests cover MTHFR?

You don’t need expensive or specialized testing to find out your MTHFR status. The MTHFR genetic variants are available in 23andMe and AncestryDNA raw data files, which are free to download if you’ve done a test with them. Here’s a quick list of inexpensive testing options:
  • 23andMe
  • AncestryDNA
  • MyHeritage
  • Sequencing .com
  • SelfDecode
  • MyGene Food
  • TellMeGen
In addition to understanding your MTHFR variants from your DNA raw data, you may also want to consider testing your homocysteine levels to see what your current status is.
Logged-in Genetic Lifehacks members are viewing details on their MTHFR variants right here.  Log in or Join now.

MTHFR: Key role in the methylation cycle

The MTHFR gene encodes an enzyme that is a key part of the methylation cycle. Methylation is the addition and removal of a methyl group (-CH3) to amino acids, DNA, and other enzymes or proteins. Within the methylation cycle, folate can be used to donate a methyl group that is used by SAMe for methylation reactions. This is a cycle that also involves homocysteine (which we will come back to in a minute).

Related article: Methylation cycle report (MTHFR, COMT, B12, and more)

Methyl groups are used to:
  1. Form new molecules, including neurotransmitters
  2. Control DNA gene expression (turn on and off genes)
  3. Detoxify certain substances
Let’s look at each of these: 1. Forming new molecules: Most of the molecules in our body are chains of hydrocarbons — carbons plus hydrogens. So adding a methyl group, a carbon plus three hydrogens, stacks on one more link in a hydrocarbon chain. The methyl group changes the original molecule into something different. A methyl group makes the molecule non-polar, which means that it isn’t able to mix with water and instead can pass through lipid membranes more easily. Example: The synthesis of melatonin involves methylation A methyl group is added to serotonin in the two-step process that forms melatonin.
The ASMT enzyme adds a methyl group to N-acetyl-serotonin to form melatonin.
  2. DNA methylation: DNA methylation is the addition of a methyl group to specific locations on a chromosome. By binding to these spots, methylation can turn genes on and off, and maintain and repair your DNA. This is an ongoing, essential, and continual use of methyl groups. 3. Detoxification and breaking down substances: Methylation is essential in the nervous system, in the production and breakdown of neurotransmitters, and in detoxifying some specific environmental toxicants such as arsenic. The folate and methylation cycle is a series of biochemical reactions that involve the transfer of methyl groups. For those who like a visual pathway, here’s what the complete folate and methylation cycle looks like. Notice that MTHFR is in a key spot, tying together 5-methyltetrahydrofolate and homocysteine. Folate and Methionine Cycle created in biorender

The MTHFR C677T and A1298C variants:

Two common variants in the MTHFR gene, C677T and A1298C, cause the enzyme not to function normally. Let’s look at what this means and the implications for your health. Understanding the terminology: The MTHFR C677T variant is a single nucleotide polymorphism (SNP). A SNP is a variation in a single nucleotide base pair (the As, Cs, Gs, and Ts) that differs from the typical nucleotide at that spot in the gene for part of the population. Similarly, A1298C is another SNP in the MTHFR gene. Both MTHFR C677T and MTHFR A1298C are common variants (SNPs). Both polymorphisms are found in approximately half the population. The substitution of a different nucleotide – the A instead of a G –  makes the MTHFR enzyme function a little differently.
Genotype and function overview
Variant/SNP Genotype Enzyme function effect Notes
C677T (rs1801133) G/G Typical No major reduction in activity.​
C677T (rs1801133) A/G ~35–40% decreased Thermolabile enzyme; more sensitive to low folate.​
C677T (rs1801133) A/A ~70–80% decreased Strongest impact on folate-dependent methylation.​
A1298C (rs1801131) T/T Typical No major reduction.​
A1298C (rs1801131) G/T Slightly decreased Mild effect alone.​
A1298C (rs1801131) G/G ~20% decreased Moderate reduction.​
Compound C677T + A1298C A/G + G/T ~50% decreased One copy of each
Let’s look at the details of what this means: What is the impact of MTHFR C677T: The MTHFR C677T variant changes the enzyme structure in a way that makes it break down faster at normal body temperature (more thermolabile). This faster enzyme breakdown then reduces the amount of enzyme available in each cell. This can be a problem when folate is limited.[ref][ref][ref]
  • One copy of the C677T variant reduces enzyme function by about 35-40%.
  • Two copies (homozygous) cause a ~70% reduction in enzyme function.
Why is it called C677T? The variant involved in C677T is a change from Cytosine (C) to Thymine (T) at position 677. This variant was originally defined on the minus strand of the DNA, but most genetic raw data files report it on the plus strand. That is why in your genetic raw data, you will see G for the typical and A for the variant, but many research studies will still include C for the typical and T for the variant. Just remember that C=G and T=A. What is the functional impact of A1298C? The A1298C variant causes less of a change to the way the enzyme works, with two copies of the variant decreasing enzyme function by around 20%. [ref] Compound heterozygous: MTHFR C677T + A1298C: Having one copy of each variant, called compound heterozygous, reduces enzyme function by around 50%. You may be wondering about what happens if someone has two copies of each variant. That is a combination that is rarely, if ever, seen (likely incompatible with life).

Research studies on MTHFR C677T or A1298C variants:

Having an MTHFR variant increases the relative risk (not certainty!) of many chronic diseases, but this does not mean it will cause you to have that disease. According to multiple meta-analyses, MTHFR C677T and A1298C increase the relative risk for high homocysteine, cardiovascular disease, stroke, neural tube defects, certain pregnancy issues, depression, migraines, and some neuropsychiatric conditions, especially with low folate/B vitamins.[ref] These same variants can lower the risk for certain conditions as well, illustrating tradeoffs of both positive and negative effects. Importantly, dietary changes or supplemental vitamins can eliminate many of the problems associated with the MTHFR variants. The MTHFR gene is extremely well researched, with over 6,000 studies investigating the C677T variant. There is also a lot of misinformation and hype about MTHFR, so this article sticks just to the high-quality studies on the topic. Studies show that the C667T and A1298C variants increase the relative risk:
  • high homocysteine, stroke, and heart disease[ref][ref][ref][ref][ref]
  • neural tube defects and cleft lip[ref]
  • preeclampsia and hypertension in pregnancy[ref][ref]
  • miscarriage[ref][ref]
  • depression or anxiety[ref][ref][ref][ref][ref]
  • Alzheimer’s and dementia (C677T only and small increase according to 2026 meta-analysis)[ref][ref]
  • autism spectrum disorder (C677T only according to 2026 meta-analysis)[ref]
  • rare problems with nitrous oxide[ref], but most have no problems[ref]
Let’s dig into the details of what research studies and clinical trials show.

Studies on MTHFR variants show:

1. Depression and the MTHFR Gene Variants: A1298C and C677T

  • A meta-analysis of 26 studies found that the MTHFR C677T variant was associated with an increased risk of depression.[ref] Age and gender may also play a role here. Postmenopausal women who carried the C677T variant had a 2 to 3-fold increased risk of depression.[ref]
  • Women with two copies of the A1298C variant were at twice the risk of major depressive disorder (MDD). The risk of MDD was even higher in people who also had COMT slow (MET) alleles. (read about COMT)[ref]
Not all studies agree, and some studies show that the MTHFR C677T variant has little to no impact on depression risk. The difference in study results could be due to diet. People who eat a diet that includes more folate (green vegetables, legumes, liver) may not be at an increased risk of mood disorders, while people who eat few folate-rich foods may be more susceptible to depression.[ref][ref]

Related article with more details: MTHFR: depression and anxiety

2. High Homocysteine  with MTHFR variants:

The methylation cycle also controls the level of homocysteine, an important marker of heart disease risk. It is also involved in cholesterol levels.[ref] Genetic variants in the methylation pathway, including MTHFR, are strongly linked to high homocysteine levels and heart disease in many studies. For example, a study in acute coronary syndrome patients showed that MTHFR C677T increased severity as well as homocysteine levels. High homocysteine is also linked to increased blood clots.[ref][ref][ref][ref]

Related article: Homocysteine- Genetics and Solutions

3. Increased risk of heart disease

Studies show a link between MTHFR C677T and an increased risk of cardiovascular disease. For example, a meta-analysis found that two copies of the MTHFR C677T variant (A/A, homozygous) increase the relative risk of heart disease by 38%.[ref][ref] However, not all studies agree, and a large prospective study (n=6,000) found that older people with two copies of the C677T allele were at a 30% decreased risk of death from cardiovascular disease when other parameters were included.[ref] The increased risk is not just due to high homocysteine. People with the C677T variant (AG or AA) have reduced endothelial function, even when homocysteine levels are normalized by increasing folate intake. The endothelium is the lining of blood vessels, and endothelial function controls how the blood vessels relax or contract to control blood pressure.[ref][ref]

Related article: MTHFR, riboflavin, and reducing high blood pressure

4. Pregnancy, infertility, and MTHFR:

One of the first researched links to MTHFR variants was neural tube defects in infants. Babies need folate for the spinal column to develop fully, and the MTHFR variants increase the risk of problems.[ref] This is why prenatal vitamins contain folate and why folic acid is added to white rice and white flour.

Related article: MTHFR, pregnancy, and infertility

5. Breakdown of estrogen, interaction with histamine:

Additionally, the methylation pathway involves the regulation of hormones, such as estrogen, and plays a role in histamine levels through breaking down high histamine.

Related article: Histamine metabolism and estrogen receptors

6. Migraines

Numerous studies show that MTHFR variants are linked to a significantly increased risk of migraines.  Some studies indicate that the risk is also due to higher homocysteine levels[ref], while other studies show that it may be due to the methylation of certain genes.[ref] Meta-analyses showed that the MTHFR C677T variant increased the risk of migraines with aura for all population ancestry groups. In non-Caucasians, the C677T variant increased migraine risk by 3-fold.[ref][ref] In North Indians, the A1298C variant was associated with the risk of migraines.[ref]

Related article: Getting to the root genetic cause of migraines

7. Detoxification and MTHFR

A methyl group is needed in the detoxification reaction for arsenic. The enzyme (arsenite methyltransferase) that metabolizes arsenic depends on the availability of methyl groups. The C677T variant is linked to decreased arsenic detoxification and increased skin lesions with exposure.[ref][ref]

Related article: Arsenic detoxification genes

Additionally, methylation is important in detoxifying mercury. In fact, MTHFR variants are tentatively linked to being more likely to have problems detoxifying mercury (small study).[ref][ref]

Related article: Mercury detoxification genes

8. Alzheimer’s and dementia risk for C677T

A 2026 meta-analysis pooled 26 studies across ethnicities to see how MTHFR variants affect Alzheimer’s and dementia risk. The results showed that the MTHFR C677T T allele increases the relative risk of both Alzheimer’s and dementia a little bit. There was no increased risk for carriers of the A1298C variant. This meta-analysis is useful because it is larger, across multiple studies, and across multiple ancestry groups.[ref]

Tradeoffs! Positive benefits of MTHFR SNPs

You may wonder why MTHFR variants – with such negative effects – are so common. It seems like a variant that should have been weeded out with natural selection. For common genetic variants, there is almost always a positive effect that balances the negatives. Plus, there are interactions between our modern world The big positive for MTHFR C677T is that it protects against several common types of cancer. Folate is needed for cell growth, especially fast-dividing cancer cells, and the decrease in folate with MTHFR variants can protect against growth in fast-growing tumors. Studies finding protective effects against cancer:
  • A meta-analysis found that two copies of the C677T variant (AA genotype) decrease the risk of colon cancer by about 20%![ref]
  • Another meta-analysis found that two copies of the C677T variant (AA genotype) were protective against prostate cancer.[ref]
  • The MTHFR C677T variant decreases the relative risk of retinoblastoma and oral squamous cell cancer.[ref][ref]
  • Two copies of the C677T variant (AA genotype) are protective against gastric cancer.[ref]
However, for someone who has cancer, the MTHFR C677T variant is associated with poorer outcomes.[ref] The MTHFR A1298C variant (GG or GT) is associated with a decreased risk of hypothyroidism according to multiple studies, meta-analyses, and trial sequential analyses.[ref][ref] The flip side: Folate can also help protect against cancerous mutations in the first place. A lack of folate is linked to double-strand DNA mutation replication. If those mutations occur in a gene important to cancer prevention, then a tumor can occur.[ref] Thus, folate helps to prevent the mutations that cause cancer, yet in someone who has cancer, folate and methyl groups can fuel cancer cell growth. Table: Risks and Benefits: Overview of MTHFR Tradeoffs
Variant Increased Risks Potential Benefits
C677T Heart disease, stroke, neural tube defects, ↓ Colon, prostate, gastric cancer
depression, migraines, pregnancy complications
A1298C Migraines, depression (with two copies) ↓ Hypothyroidism

Gene expression and MTHFR:

MicroRNAs are short strands of RNA that can bind to an mRNA strand and block it from being translated into its protein. In cell studies, folate deficiency upregulates miR-22 and  miR-149. These two miRNAs bind to the MTHFR mRNA and keep it from being turned into the MTHFR enzyme when folate is lacking. Interestingly, the effects of folate deficiency regulate miRNA differently in cancer cells vs. non-cancerous cells. Those same miRNAs also affect tumor suppressor genes.[ref] While a lot more research is needed here, the impact of miRNA on both tumor suppressors and MTHFR may be part of why folate is both beneficial for preventing cancer and then detrimental during some types of cancer.

Lifehacks: Diet and Supplements for MTHFR

Knowing that you carry an MTHFR genetic variant can help guide your choice of foods and supplements. By optimizing your diet, you can easily mitigate the risks from the MTHFR variants.[ref] Let’s explore some diet and supplement options for individuals with MTHFR variants.

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Digging deeper: MTHFR is more than just C677T and A1298C

While the C677T and A1298C are the most well-studied variants, there are several other genetic variants in the MTHFR gene that either increase or decrease the enzyme’s function.

Genotype report: Additional MTHFR variants

Additional variants to check that decrease MTHFR enzyme function:

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Related B Vitamins and Methylation

Frequently Asked Questions (FAQ) About MTHFR:

What is the MTHFR gene, and what does it do?

The MTHFR gene codes for an enzyme (methylenetetrahydrofolate reductase) that converts folate (vitamin B9) into its active form. Why it matters: This process produces methyl groups used for:
  • DNA methylation (gene regulation)
  • Neurotransmitter synthesis (brain health)
  • Detoxification (removing toxins)
  • Heart health (managing homocysteine)

What are the most common MTHFR variants?

The two most common variants are C677T and A1298C. These are single nucleotide polymorphisms (SNPs), not rare mutations, and are found in about half the population.

How can I check if I have an MTHFR variant?

You don’t need expensive genetic testing. You can check your raw data from 23andMe or AncestryDNA for the C677T (rs1801133) and A1298C (rs1801131) SNPs.

What do the C677T and A1298C results mean for enzyme function?

C677T:
  • G/G: typical function
  • A/G: enzyme function decreased by ~40%
  • A/A: enzyme function decreased by 70–80%
A1298C:
  • T/T: typical function
  • G/T: slightly decreased function
  • G/G: enzyme function decreased by ~20%

Are there other MTHFR variants that matter?

Yes, variants like G1793A (rs2274976) can also significantly decrease enzyme function, while others, such as rs9651118 and rs13306560, are associated with positive health outcomes like lower blood pressure or reduced risk of certain diseases.

How do MTHFR variants affect my health?

Variants like C677T and A1298C can reduce enzyme efficiency, potentially leading to higher homocysteine levels and impacting processes like detoxification, neurotransmitter production, and cardiovascular health.

What can I do if I have an MTHFR variant?

Optimizing your diet is key. Increase intake of natural folate (leafy greens, lentils, liver, asparagus, broccoli), choline (egg yolks, beef liver, wheat germ), and betaine (beets, quinoa, spinach). These nutrients can help mitigate the risks associated with reduced enzyme function.

Is folate the same as folic acid?

No. Folate is the natural form found in foods, while folic acid is a synthetic form used in supplements and fortified foods. Not everyone with MTHFR variants processes folic acid efficiently, so focus on natural food sources of folate.

Can increasing dietary folate help with MTHFR?

Yes. Studies show that increasing folate-rich foods can lower homocysteine and inflammatory markers, especially in people with the C677T variant.

Do MTHFR variants affect both men and women?

Yes. For example, MTHFR variants in fathers can also affect fertility and miscarriage risk Dads and MTHFR.

Should I get MTHFR testing done?

Understanding your MTHFR variants can help you dial in your diet and prevent many age-related chronic conditions. Fortunately, the MTHFR SNPs are readily available in your raw data if you’ve already done genetic testing, such as through 23andMe or AncestryDNA.

What should I eat if I have MTHFR C677T?

Optimizing your diet to include plenty of natural sources of folate helps to mitigate the negative effects of the MTHFR variants. Folate-rich foods include leafy greens, lentils, many green vegetables, and liver. Vitamin B12 is also important, along with other B vitamins. Vitamin B12 is only found in animal-based foods, so people eating a primarily vegan diet may need to consider supplementing with a B-complex. Talk with your healthcare provider if you have questions about this.

What does compound heterozygous mean?

When an article on MTHFR mentions ‘compound heterozygous’, it refers to having one copy of the MTHFR C677T variant and one copy of the A1298C variant. This combination reduces the efficiency of the folate-related enzyme by about 50% and makes it important to consume plenty of folate-rich foods in the diet.

Is MTHFR dangerous?

While the variants in MTHFR increase the relative risk of several chronic conditions, they do not cause a specific disease on their own. Instead, it is a combination of diet and environment, which interacts with increased susceptibility due to the MTHFR variants. Recap of your genes:
GeneRS IDYour GenotypeNotes for Your GenotypeEffect alleleEffect allele frequency
MTHFR rs1801133 — typicalone copy of MTHFR C677T allele, enzyme function decreased by 40%two copies of MTHFR C677T, enzyme function decreased by 70 – 80% A 0.33
MTHFR rs1801131 — typicalone copy of MTHFR A1298C (heterozygous), slightly decreased enzyme function by ~10-20%two copies of MTHFR A1298C (homozygous), decreased enzyme by about 20-30% G 0.3
MTHFR rs2274976 — typicalsomewhat increased risk of schizophrenia, cognitive issues possible for seniors with this genotype in conjunction with low vitamin B12associated with cleft lip, neural tube defect, higher homocysteine, and folate deficiency, increased risk of schizophrenia in children, cognitive issues possible for seniors with this genotype in conjunction with low vitamin B12, risk of lower bone mineral density if B12 is also low T 0.04
MTHFR rs4846048 — typicalincreased relative risk of cervical cancer through miR-522 interactionincreased relative risk of cervical cancer through miR-522 interaction G 0.3
MTHFR rs9651118 — most common genotypedecreased risk of liver cancer, slower cognitive decline in the elderly, lower homocysteine, type 2 diabetes (compared to T/T)decreased risk of lung cancer, lower homocysteine, type 2 diabetes (compared to T/T) C 0.2
MTHFR rs13306560 — typicalavg 2.6 mmHg lower diastolic blood pressureavg 5.2 mmHg lower diastolic blood pressure, protective against Parkinson’s T 0.05
MTHFR rs17367504 — typicalprotective against hypertension, preeclampsiaprotective against hypertension, preeclampsia G 0.14
MTHFR rs4846049 — decreased risk of migraines, lower relative risk of cervical cancertypicaltypical, most common genotype G 0.61

Related Articles and Topics:

Histamine Intolerance, MTHFR, and the Methylation Cycle

References:

References

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About the Author:
Debbie Moon is a biologist, engineer, author, and the founder of Genetic Lifehacks where she has helped thousands of members understand how to apply genetics to their diet, lifestyle, and health decisions. With more than 10 years of experience translating complex genetic research into practical health strategies, Debbie holds a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. She combines an engineering mindset with a biological systems approach to explain how genetic differences impact your optimal health.