MTHFR C677T vs. A1298C: What’s the Practical Difference?

If you've had genetic testing and discovered an MTHFR variant, there's a good chance your report mentions one or both of two names: C677T and A1298C. These are both variances in the same gene, MTHFR, but these two variants aren't the same (see the magic chair analogy for a simple explanation). They affect the MTHFR enzyme differently, and their practical significance can vary considerably.

What Does MTHFR Do?

The MTHFR gene provides instructions for making the enzyme methylenetetrahydrofolate reductase (also called the MTHFR enzyme). This enzyme plays an important role in folate metabolism. MTHFR helps convert 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (5-MTHF), a biologically important form of folate used in the remethylation of homocysteine to methionine. Methionine can then contribute to production of S-adenosylmethionine, or SAM, an important methyl donor used throughout the body. That means MTHFR sits at an important intersection between folate metabolism, homocysteine regulation and methylation.

Having an MTHFR variant does not automatically mean that your methylation is not working or that you have a disease. C677T and A1298C are both common genetic polymorphisms. They are very different from the rare, severe mutations that can cause true MTHFR enzyme deficiency. One of the most common questions I hear from community members is "Which one is worse - MTHFR C677T vs. A1298C?" So let's look at what these variances really mean.

MTHFR C677T: The Most Researched Variant

MTHFR C677T, also known as rs1801133, changes the structure of the MTHFR enzyme and makes it more thermolabile, meaning the enzyme is less stable. You inherit one copy of the MTHFR gene from each parent, so your C677T result may be:

• CC: no 677T copies - this is "wild-type" or normal

• CT: one 677T copy, or heterozygous

• TT: two 677T copies, or homozygous

The original research identifying this variant demonstrated reduced MTHFR enzyme activity in people carrying the T allele, with the greatest reduction occurring in those with the TT genotype. Importantly, though, genotype isn't the whole story, and simply having any of these genetic variants doesn't indicate anything about your health. The biochemical effects of C677T are strongly influenced by folate status. People with the 677TT genotype tend, on average, to have lower blood folate and higher homocysteine than people with CT or CC genotypes, particularly when diet is poor.

A meta-analysis of folate intervention studies found that people with the TT genotype had higher baseline homocysteine and lower serum folate than those with CC or CT genotypes. Folate supplementation improved homocysteine across genotypes, although folate responses differed somewhat by genotype. This higher level of homocysteine has been associated with conditions such as Alzheimer's dementia and cardiovascular disease.

This polymorphism (see SNPedia for the full list) has shown associations in at least one study with the following conditions (although not always reproduably):

• autism

• cancer, including

  • breast cancer

  • colorectal cancer (risk reduction)

  • gastric cancer

  • lung cancer

  • head and neck cancer

  • brain cancer

  • renal cancer

• cleft lip and cleft palate

• coronary artery disease

• dementia

• depression

• hyperhomocysteinemia

• infertility

• liver toxicity with methotrexate treatment

• migraine and cluster headache

• neural tube defects

• osteoporosis

• parkinsons disease

• pre-eclampsia (gestational hypertension)

• schizophrenia

• thrombosis

• down syndrome

What about A1298C?

A1298C, or rs1801131, is another common MTHFR variant. Its possible combinations are:

• AA: no 1298C copies, meaning "wild type" or normal genes

• AC: one copy of the gene variant

• CC: two copies of the gene variant

A1298C also affects MTHFR enzyme activity, but its biochemical effects appear to be different from those of C677T. In one of the foundational studies of A1298C, researchers found that enzyme activity decreased with the C variant, particularly in people with two copies. However, unlike C677T homozygosity, A1298C by itself was not associated with significantly elevated homocysteine or lower plasma folate in that study.

Other studies have similarly found a much clearer relationship between C677T and homocysteine than between A1298C and homocysteine. That doesn't make A1298C meaningless. It simply means we shouldn't assume that every MTHFR variant has the same metabolic consequences. Interestingly, we have a lot less data on what MTHFR A1298C actually does in the human body because the research primarily focuses on homocysteine-related diseases. Because of this, A1298C remains slightly mysterious. It is easy to assume that is it not as consequential as C677T, but it could just be that the consequences aren't as logically obvious as elevated homocysteine. There is clearly some kind of relationship wtih MTHFR A1298C and blood clotting (see the list of conditions below) and also with a tendency towards neurological issues (diabetic neuropathy, glaucoma, parkinsons).

This polymorphism (see SNPedia for the full list and research references) has shown associations in at least one study with the following conditions (although not always reproduably):

• blood clootting (venous thromboembolism)

  cancer, including

  • brain cancer

  • breast cancer

  • colorectal cancer (risk reduction)

• diabetic neuropathy

• glaucoma

• ischemic stroke (caused by blood clots)

• Alzheimer's dementia (some studies show increased risk, some show protective effect)

• radiation pneumonitis in lung cancer patients treated with radiation (possible larger suceptibitilty to problems from radiation exposure)

• blood clotting in lupus patients

• parkinsons disease

• male infertility

• congenital heart defects (reduced risk)

  
  

MTHFR C677T vs. A1298C - Which One Is “Worse”?

This is where genetic conversations get weird. Neither variant should automatically be described as “good” or “bad.” Many people with these variances will never know they have them, but others are strongly affected because of other genes, diet, lifestyle, toxin exposures, or other factors. The consequences of these gene SNPs are so variable, that it is often more useful to look at the symptoms you have, rather than the genes you were born with. In general, the research evidence suggests this pattern in the great MTHFR C677T vs. A1298C debate:

Genotype	Typical biochemical significance
677 CT	Mild reduction in MTHFR activity; often little biochemical effect when nutrient status is adequate but linked to higher homocysteine and lower folate levels
677 TT	Greater reduction in activity; more consistently associated with lower folate and higher homocysteine
1298 AC	Usually modest biochemical effect (in terms of homocysteine and folate, because those are the things we're looking for)
1298 CC	Reduced enzyme activity, but not consistently associated with elevated homocysteine. Some clear disease associations
One 677T + one 1298C	Produces a greater reduction in MTHFR activity than either single heterozygous variant alone, and is poorly understood.

These are population-level patterns but not predictions of exactly what will happen in an individual. Individuals have all the variability of external factors like nutrition and toxin exposure that must be taken into account.

What Does Compound Heterozygous Mean?

Someone who carries one C677T variant and one A1298C variant is often described as compound heterozygous. Early research found that people carrying one copy of each variant could have lower MTHFR activity, higher homocysteine and lower folate than people carrying just one heterozygous variant. But even here, the genotype should not be treated as a diagnosis. Your actual homocysteine level and nutritional status tell us far more about what is happening right now than your genetic result alone.

I Have MTHFR. Now What?

If an MTHFR result shows C677T or A1298C, resist the temptation to immediately build an elaborate supplement protocol around the SNP. Take a breath - this isn't the time to dive into a complicated supplement routine, it's the time to find out how this is affecting you, and more importantly, how you can balance your health with this gene variance (or gene SNP) in mind to prevent future health problems.

Depending on your state of health, useful tests include:

• Homocysteine

• Folate status

• Vitamin B12 status

• Riboflavin status

• Vitamin B6

• Kidney and thyroid function when clinically relevant

If any of these tests come back abnormal, dive into the research in that particular area and work with your doctor or a knowlegable practitioner to address that particular problem.

Also, assess these for yourself:

• Medications that affect folate or homocysteine metabolism (there are many!)

• Alcohol intake, smoking and other lifestyle factors

• Dietary natural folate intake vs. dietary synthetic folic acid intake

Riboflavin deserves particular attention because vitamin B2 is used to produce FAD, the cofactor required by the MTHFR enzyme. Research suggests an interaction among folate, riboflavin, MTHFR function and homocysteine metabolism. The MTHFR enzyme, no matter what MTHFR genes you have, can not function without a cofactor, so riboflavin is an often overlooked piece of the puzzle.

Genes Can't Explain Everything

Perhaps the biggest mistake we can make with MTHFR testing is turning a common genetic variant into an explanation for every symptom. C677T and A1298C can provide useful information about how your folate pathway may function, but they don't tell us whether you have adequate folate, whether homocysteine is elevated, whether methylation is impaired, or whether a particular supplement is necessary.

Your gene SNPs are an important piece of the picture regarding your overall health, and especially in terms of proactively maintaining your health against future risks, but it isn't as simple as one SNP = one health problem.

References

** This list is partial. If you are looking for the source of particular information in this article, please reach out to me via the contact form.

Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics. 1995;10(1):111–113. doi:10.1038/ng0595-111. PMID: 7647779.

van der Put NMJ, Gabreëls F, Stevens EMB, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? American Journal of Human Genetics.1998;62(5):1044–1051. doi:10.1086/301825. PMID: 9545395.

Colson NJ, Naug HL, Nikbakht E, Zhang P, McCormack J. The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies. European Journal of Nutrition. 2017;56(1):247–260. doi:10.1007/s00394-015-1076-x. PMID: 26497154.

Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. American Journal of Clinical Nutrition. 2015;101(6):1286–1294. doi:10.3945/ajcn.114.099994. PMID: 25788000.

Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine. 2013;15(2):153–156. doi:10.1038/gim.2012.165. PMID: 23288205.

Pereira AC, Schettert IT, Morandini Filho AA, Guerra-Shinohara EM, Krieger JE. Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine-folate correlation in a mild folate-deficient population. Clinica Chimica Acta. 2004;340(1–2):99–105. doi:10.1016/j.cccn.2003.09.016. PMID: 14734201.

Moat SJ, Ashfield-Watt PAL, Powers HJ, Newcombe RG, McDowell IFW. Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype. Clinical Chemistry.2003;49(2):295–302. doi:10.1373/49.2.295. PMID: 12560354.