MTHFR: Going Beyond C677T and A1298C

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

But there is more to the MTHFR story than just those two variants!

This article gives you the bigger picture, including MTHFR variants with positive or protective outcomes.

Going beyond MTHFR 677 and 1298

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.

In a nutshell, the methylation cycle is a cellular cycle responsible for creating methyl groups (CH3). These methyl groups are used by the body in tons of different reactions as well as to modify gene expression. Thus, alterations to the availability of methyl groups can have a wide range of impacts.

When reading about MTHFR, most articles only cover the C677T and A1298C variants. But those two variants do not give the whole picture for the MTHFR gene. Other variants also impact the way the MTHFR enzyme functions – both positively and negatively.

Also, keep in mind that diet is important here. Many of the impacts of MTHFR variants are mitigated through a diet rich in folate or choline.[ref]

MTHFR Genotype Report:

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Variants that decrease MTHFR enzyme function:

In addition to the MTHFR C677T and A1298C variants, the G1793A variant also significantly decreases 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
  • C/T: decreased risk of liver cancer[ref], slower cognitive decline in elderly[ref], lower homocysteine, type 2 diabetes (compared to T/T)[ref][ref]
  • C/C: decreased risk of lung cancer[ref], lower homocysteine, type 2 diabetes (compared to T/T)[ref][ref]

Members: Your genotype for rs9651118 is .

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

  • T/T: avg 5.2 mmHg lower diastolic blood pressure[ref], Protective against Parkinson’s[ref]
  • C/T: avg 2.6 mmHg lower diastolic blood pressure
  • C/C: typical

Members: Your genotype for rs13306560 is .

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

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

Members: Your genotype for rs17367504 is .

Check your genetic data for rs4846049 (23andMe v4; AncestryDNA):

  • G/G: decreased risk of migraines[ref], lower relative risk of cervical cancer[ref]
  • G/T: typical
  • T/T: typical, most common genotype

Members: Your genotype for rs4846049 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

Read more: Folate-rich foods and recipe ideas

If you don’t eat enough folate-rich foods regularly, methylfolate supplements are also available. The RDA for folate is 400 mcg/day for adults (600 mcg/day for pregnancy). Tracking your folate intake using an app, such as Cronometer, for a week or two should give you a good idea of how much folate you regularly eat.

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 works via the methylation cycle; therefore, food sources of betaine (beets, quinoa, and spinach) are also helpful here. Supplemental betaine (also called TMG) is also available.

Read more: Choline-rich foods and recipes

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.

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