MTHFR – Beyond C677T and A1298C

Going beyond MTHFR 677 and 1298

The MTHFR C677T and A1298C variants get a lot of press  – from Facebook groups to whole websites that talk about them.

MTHFR is a key gene in regulating the body’s folate metabolism. The folate cycle interacts with the methylation cycle, supplying the body’s need for methyl groups.

I’m assuming that you already know a little about the methylation cycle and the MTHFR C677 and A1298C variants. If you don’t know your status on those two, check out this page: MTHFR: How to check your data for C677T and A1298C  and read through the background information on the methylation cycle.

But the C677T and A1298C variants do not give the whole picture for the MTHFR gene. There are additional variants that also impact the functionality of the enzyme.


Additional MTHFR Genetic Variants:

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Variants that decrease MTHFR enzyme function:

Check your genetic data for rs2274976 G1793A or R594Q (23andMe v4, v5; AncestryDNA) known as :

  • T/T: associated with cleft lip, OR 3.46[ref] neural tube defect[ref], higher homocysteine, and folate deficiency[ref] increased risk of schizophrenia in children[ref][ref] cognitive issues possible for seniors with this genotype in conjunction with low vitamin B12[ref]
  • C/T: somewhat increased risk of schizophrenia, cognitive issues possible for seniors with this genotype in conjunction with low vitamin B12[ref]
  • C/C: typical

Members: Your genotype for rs2274976 is .


Variants that are associated with positive outcomes:

Check your genetic data for rs9651118 (23andMe v4; AncestryDNA):

  • T/T: most common genotype; relatively higher homocysteine, higher risk of T2D[ref][ref]
  • C/T: decreased risk of liver cancer[ref] slower cognitive decline in elderly[ref]
  • C/C: decreased risk of lung cancer[ref]

Members: Your genotype for rs9651118 is .


Check your genetic data for rs13306560 (23andMe v4; AncestryDNA):

  • A/A: avg 5.2 mmHg lower diastolic blood pressure[ref] Protective against Parkinson’s[ref]
  • A/G: avg 2.6 mmHg lower diastolic blood pressure
  • G/G: typical

Members: Your genotype for rs13306560 is .


Check your genetic data for rs17367504 (23andMe v4, v5; AncestryDNA):

  • G/G: protective against hypertension, preeclampsia[ref]
  • A/G: protective against hypertension, preeclampsia
  • A/A: typical

Members: Your genotype for rs17367504 is .



If you have variants that decrease your methylation cycle function, you may want to bring your levels up to the normal range.

Increase your folate intake:

Foods that are high in folate include:[ref]

  • Beef liver
  • Lentils, black-eyed peas
  • Spinach
  • Broccoli
  • Avocados

If you don’t eat enough folate-rich foods on a regular basis, methylfolate supplements are also available. The RDA for folate is 400 mcg/day for adults (600 mcg/day for pregnancy).

Choline-rich foods:

Choline can help your body bypass a lack of folate in the methylation cycle.[ref ][ref ]

Good sources of choline include egg yolks, beef liver, and wheat germ. A metabolite of choline, betaine, is actually what is working through the methylation cycle, therefore food sources of betaine (beets, quinoa, and spinach) are also helpful here. Supplemental betaine (also called TMG) is also available.

Supplemental Methyl Folate and B12:

If you aren’t getting enough folate from foods, you could try a low-dose methyl folate supplement. Vitamin B12 is also important in the methylation cycle, so you need to ensure you are getting enough B12 either through diet or supplements.

People who have COMT genetic variants may want to be careful about high-dose supplements that affect the methylation cycle. Read all about COMT and check your genes.

Riboflavin (vitamin B2):

The MTHFR C677T variant decreases its ability to bind to FAD, a riboflavin-dependent enzyme.[ref] If you have high homocysteine (a marker for heart disease risk), a couple of studies show that adding riboflavin lowers homocysteine levels in those with the A/A genotype.[ref][ref] Other research points to riboflavin lowering homocysteine levels only if vitamin B6 levels are adequate.[ref]

Related Articles and Genes:

Top 10 Genes to Check in Your Genetic Raw Data
It can be overwhelming when you are getting started with learning how your genes affect your health. What is actually important? Does it really matter if something increases your risk of an obscure disease by 10%?

Choline – An Essential Nutrient
Choline is an essential nutrient that a lot of us don’t get enough of. In fact, the majority of the US population doesn’t get enough choline on a daily basis. Insufficient choline can impact mental sharpness, heart health, fatty liver disease, and more.

Should you take folic acid if you have MTHFR variants?
There is a lot of buzz online about MTHFR variants and the need to avoid folic acid. I’ve seen recommendations ranging from avoiding all processed foods that are fortified with folic acid — to recommendations that people with MTHFR variants need to take extra folic acid.

Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.