Everything You Need To Know About The MTHFR Gene Variants, According To Experts

If you've read anything about the emerging fields of personalized medicine or precision nutrition—or used an at-home genetic test kit to learn about your ancestry or inherited health traits—you've probably heard about MTHFR genetic variants. And no, it's not shorthand for your favorite expletive.  

These genetic variants (known more scientifically as single nucleotide polymorphisms, or SNPs) have gained attention for the way they affect your ability to process and use the essential B vitamin folate and, thereby, affect a globally important (i.e., literally affects whole-body health) biochemical process called methylation.

Before we dive into the genetic variants and what they mean, let's talk about MTHFR itself and its role in the body when everything is functioning optimally. 

This activated folate acts as a highly effective and required methyl donor and plays a key role in a biochemical process called methylation—i.e., the transfer of methyl groups (simple structures of one carbon and three hydrogen molecules) to and from different compounds to support overall health.*

Specifically, 5-MTHF donates a methyl group1 to the amino acid homocysteine to convert it to the amino acid methionine; and methionine, in turn, can be activated to form S-adenosylmethionine (SAM-e), which travels around the body donating methyl groups to a variety of acceptors and helping regulate the activity of our cardiovascular, neurological, reproductive, and detox systems in the process.* 

Holistically, this process or path is known as the methylation cycle. And as Ashley Jordan Ferira, Ph.D., RDN, mbg's vice president of scientific affairs, explains, "that first step—bioactive folate donating a methyl group to transform homocysteine to methionine—is a rate-limiting step."*

What does that mean? Ferira shares more: "It means that without adequate methylated folate (5-MTHF) hanging around, homocysteine can't move along efficiently to its next critical step. It can build up, and the rest of the methylation cycle is also slowed or deprived as a result. As it turns out, that's a huge deal for your health."*

The MTHFR gene provides instructions for the body to make the MTHFR enzyme. "Just like there are different alleles for all kinds of genes that contribute to the unique human you are, the same is true for gene variants that impact nutrients and their metabolism," explains Ferira. For MTHFR, there are two common variants or SNPs (changes in the DNA sequence) that affect the enzyme's activity. This means that MTHFR is less efficient at converting folate and folic acid into the active 5-MTHF form. 

The most common variant in the MTHFR gene is called C677T. About 20 to 40% of white and Hispanic individuals in the U.S. have one copy of C677T, which reduces enzyme function by approximately 35%, while 8 to 20% of the population has two copies of C677T (one from each parent), which reduces enzyme function by up to 70%.

Another variant called A1298C is found in about 7 to 12% of the North American population and carrying two copies may reduce enzyme function by 40%. In total, approximately 150 million Americans have an MTHFR gene variation—that's 50% of the population!

Because the MTHFR enzyme is less active with these variants, this can directly contribute to poor conversion to active folate (5-MTHF), which can mean your methylation cycle isn't running efficiently or optimally. As Ferira alluded to earlier and echoed by Rountree, this may cause subsequent elevations in homocysteine.

But just because you have an MTHFR gene variant doesn't necessarily mean you'll experience health issues, emphasizes Rountree. "Having a genetic variant generates a hypothesis, and then you have to test that hypothesis by looking for biomarkers," he says. "Testing homocysteine levels is the one reliable marker we have to determine if we're getting enough folate to support optimal methylation."*

"Not everyone with MTHFR SNPs will have subpar methylation or functional folate status; however, the combination of an MTHFR SNP and a typical American diet will often lead to methylation issues," says functional medicine physician Karyn Shanks, M.D., who openly shared that she possesses a copy of the C677T gene variant.

Testing for MTHFR variants is not widely recommended, unless you have excess levels of homocysteine. Unfortunately, it's not a genetic test commonly covered by health insurance. So if you're curious about your MTHFR status, Rountree suggests starting with a homocysteine test. It's a relatively cheap and easy blood test, and it can guide further testing.

"If homocysteine levels are subpar, then even if you do have a genetic variant, your body is handling it," says Rountree. If the opposite is true, and you're eating a healthy diet, he adds, "it's time to ask yourself, 'I wonder if there's a genetic reason for that?'"

In functional and integrative medicine, homocysteine levels less than 7 μmol/L2 are often considered optimal. But as Ferira explains, "Any biomarker range can be honed to optimize the individual's health when partnering closely with a health care practitioner, but generally speaking, the normal range for homocysteine is broader and also age-dependent. Most adults want to aim for less than 15 μmol/L." For older adults, the upper end of the normal range expands a bit (up to 21 μmol/L).

The MTHFR enzyme maintains a certain level of activity even when you have a genetic variant—it's just less efficient. Increasing folate intake from dietary sources may help compensate by increasing levels of overall folate in the body, according to registered dietitian Ali Miller, R.D. Folate-rich foods include leafy greens, broccoli, avocado, asparagus, beets, citrus, animal proteins (particularly beef liver), and legumes. 

However, as Ferira further explains, "while food folate is great—and oh, by the way leafy greens and similar plants are chock full of other nutrients and phytonutrients too—the folate naturally intrinsic to foods is in the tetrahydrofolate form, while fortified foods have folic acid. To be clear: Neither of those are fully activated 5-MTHF folate. They require several conversion steps, one of which is via your MTHFR enzyme to be fully activated."

That's why taking a supplement that already contains the bioactive form of folate—5-MTHF, aka methylfolate—can help your body absorb and utilize this essential B vitamin more readily and fully than supplements containing regular (not methylated) folic acid.* Rountree has been using and recommending methylfolate in his clinical practice for the past 20 years. 

Ferira explains that she also recommends methylated folate and other bioactive B's too, saying that approach helps "clear the noise of genetic variation and deliver effective nutrition solutions that are inclusive to everyone's genetic makeup."* Miller agrees, adding that methylfolate is the most directly beneficial supplement for people with this variant, but "other methyl donors can be helpful as well, such as methylcobalamin (methylated form of B12), B6, and choline."* Choline is a precursor to betaine, a major methyl donor in this methylation story.*

MTHFR genetic variants are extremely common (and thus, we think should be discussed more!) and can affect the conversion of dietary folate and folic acid into active 5-MTHF. In some individuals, this may not manifest in tangible ways, while in others it could cause a deficit of functional folate and affect the whole-body process of methylation, leading to extra homocysteine and more.