MTHFR is a commonly searched genetic term in Australia, and a frequently misunderstood one. Online wellness content often links it to a wide range of concerns, from fatigue and mood to fertility. The evidence tells a more modest story. The two common MTHFR variants are very common, they affect one specific step in folate metabolism, and Australian medical bodies currently advise against routine MTHFR testing in clinical practice [1,2]. Both things can be true at once: MTHFR is interesting biology, and it isn't the diagnostic explanation it's sometimes presented as.
This guide covers what MTHFR is, what a variant means genetically, what the research does and doesn't show, what testing involves, and what professional bodies currently say about its clinical usefulness.
What is MTHFR, and what does it do?
MTHFR (methylenetetrahydrofolate reductase) is an enzyme in the folate pathway. Folate is a B vitamin, and MTHFR carries out one step in converting it into 5-methyltetrahydrofolate, the main form of folate circulating in the blood. This form helps the body recycle homocysteine, an amino acid, into methionine, a process that also relies on vitamin B12 [3]. Methionine in turn supports methylation, a chemical process the body uses for many routine tasks, including regulating gene activity and making some neurotransmitters. Folate is also needed to make and maintain DNA.
The MTHFR gene, which carries the instructions for making this enzyme, has two common, well-studied variants: C677T and A1298C. The C677T variant reduces enzyme activity, more noticeably in people who carry two copies, while A1298C has a smaller effect [4-6]. This reduced activity is the biochemical basis for interest in MTHFR testing, but lower enzyme activity measured in a laboratory does not, on its own, translate into poorer health.
These common variants are different from severe MTHFR deficiency, a rare inherited metabolic condition caused by other, uncommon changes in the gene [3,6]. Severe deficiency is diagnosed and managed through specialist clinical services, and it is not what consumer MTHFR tests are designed to identify.
How common are MTHFR variants?
Very common. Around two in three people carry at least one copy of C677T or A1298C, and roughly 1 in 10 carry two variant copies [3,7]. Frequencies vary with ancestry: for example, 10 to 15% of North Americans of European ancestry, and more than 25% of Hispanic people, carry two copies of C677T [5]. Having a variant is a normal, frequent genetic finding rather than a rare abnormality, and most people who carry one have no related health problem.
What does the research actually show?
What is well established:
- People with two copies of C677T tend to have mildly higher homocysteine levels on average, around 20% higher, mainly when their folate intake is low [5,8]. The difference is smaller when folate intake is adequate, as it is for most people in countries with folate fortification.
- Folic acid, the form used in supplements and added to Australian bread-making flour, raises folate levels in people who carry MTHFR variants [9,10]. People with two copies of C677T tend to have lower blood folate and may respond a little less to supplements, but in folic acid studies their homocysteine levels ended up similar to everyone else's [9].
What remains uncertain or unsupported:
- Researchers have looked for links between MTHFR variants and many conditions. Large, well-designed studies have found little or no link with heart disease or blood clots [8,11]. Some studies report modest links with neural tube defects and with some mental health conditions, and the evidence for pregnancy loss is weak [1,5,12]. These are small differences seen across large groups of people. They don't predict an individual's risk, and they are not considered strong enough to guide diagnosis or treatment [1,5].
- Both folic acid and "activated" folate such as methylfolate raise blood folate levels [13,14]. Folic acid is the form proven in clinical trials to help prevent neural tube defects, and there is currently no evidence that methylfolate leads to better health outcomes for people with MTHFR variants [10,15].
What professional medical bodies currently say
This is the part most MTHFR content skips, and it's the part that matters most for making sense of a result.
The Royal Australian College of General Practitioners (RACGP), in its guide "First do no harm: a guide to choosing wisely in general practice", advises GPs not to routinely order MTHFR gene testing. It notes there is no established causal link between the common MTHFR variants and particular diseases, and no evidence-based treatment shown to improve outcomes for people who carry them, so a result is unlikely to change how a GP manages a patient. It also advises against MTHFR testing when investigating blood clotting disorders (thrombophilia) or early pregnancy loss [1]. The Human Genetics Society of Australasia, through Choosing Wisely Australia, also recommends against MTHFR genetic testing [2].
The Royal College of Pathologists of Australasia (RCPA) has published a position statement concluding that there is insufficient evidence of benefit to recommend MTHFR testing as a basis for medical decisions in people who eat a normal, folate-fortified diet [16]. In Australia, folic acid has been added to wheat flour for bread-making (except organic flour) since 2009, so most people who regularly eat bread get some folic acid through their diet [17].
Folate advice before and during pregnancy is the same regardless of MTHFR status [1,5]. Australian advice is to take a daily supplement containing at least 400 micrograms of folic acid from at least one month before conception until three months into pregnancy, to help reduce the risk of neural tube defects [15,17]. Some people are advised to take a higher dose, for example those with diabetes, a higher body weight, a previous pregnancy affected by a neural tube defect, or who take certain medicines [18]. This is decided with a doctor. An MTHFR result does not change this advice in either direction.
What a positive result does, and doesn't, mean
A positive MTHFR result means you carry one or two copies of one or both common variants. It is information about your genetics. On current evidence, it does not mean you have a medical condition, that a particular symptom or health problem is explained by it, or that a specific treatment, supplement or diet is medically indicated [1,5].
Homocysteine, the blood marker often discussed alongside MTHFR, can be measured directly with a blood test. Raised homocysteine has a number of possible causes, including low vitamin B12, folate or vitamin B6, reduced kidney function and some medicines [19], and a GP can assess it without needing an MTHFR result. Large trials of B-vitamin supplements to lower homocysteine have not reduced heart attacks, although a major review found a small reduction in stroke [20].
How MTHFR testing works, if you want to explore it
For people who want to understand their own genetics out of general interest, i-screen offers two testing formats:
- MTHFR Blood Test, a blood sample testing for the C677T and A1298C variants.
- MTHFR Cheek Swab Test, the same two variants, from an at-home cheek swab with no blood draw required.
Both can be ordered online without a GP referral. Given the evidence summarised above, results are best viewed as general genetic information to discuss with a GP or practitioner if you have specific questions, rather than as a basis for starting or changing any treatment, supplement or diet on your own.
If your interest is in the broader methylation pathway rather than MTHFR specifically, our Genetic Methylation Test covers MTHFR alongside seven related methylation genes, and our guide to methylation types explores that wider picture. Testing for these other methylation genes is not part of routine clinical care, and results are not currently used to diagnose conditions or guide treatment.
The honest bottom line
MTHFR variants are common, interesting from a biology standpoint, and not currently supported by Australian medical bodies as a basis for routine clinical decisions [1,2,16]. That doesn't make the science uninteresting. It means being clear about what a result can and can't tell you. If you're curious about your own genetics, that's a reasonable thing to explore. If you're trying to understand a specific health concern, that's a conversation for your GP, with or without an MTHFR result in hand.
This article is general information only and does not replace advice from your doctor. The common MTHFR gene variants are not, on current evidence, an established cause of specific health conditions. The Royal Australian College of General Practitioners advises against routine MTHFR testing, and the Royal College of Pathologists of Australasia considers there is insufficient evidence of benefit to base medical decisions on it. Do not start, stop or change any medicine, supplement or treatment based on an MTHFR result without discussing it with your doctor. Anyone planning a pregnancy or who could become pregnant should follow standard folic acid advice regardless of MTHFR status, and check with their doctor about the right dose for them.
