MTHFR
The MTHFR variants, explained plainly
The most talked-about gene in nutrigenomics, and the most misunderstood. What the variants do, who has them, and how we work with them.
The four common patterns
MTHFR is the enzyme that turns folate into its active form, 5-MTHF. Two common variants slow it down. Neither is a disease, but both change what your body needs from food and supplements. Roughly 60 percent of people carry at least one.
C677T, one copy heterozygous · ~35–40% of people
Enzyme activity is reduced by roughly a third. Most people notice nothing unless folate, B12 or B2 intake is low, at which point homocysteine can creep up and energy and mood can suffer.
C677T, two copies homozygous · ~10% of people
Activity can drop to around 30 percent of normal. This is the variant most consistently linked to elevated homocysteine, and the one where the choice of folate form matters most.
A1298C one or two copies · ~30% of people
A milder variant that affects a different part of the enzyme. On its own it rarely raises homocysteine, but it is often discussed in relation to BH4, a cofactor for making serotonin and dopamine.
Compound heterozygous one C677T + one A1298C · ~15–20%
One copy of each. The combined effect can approach that of two C677T copies, so we treat it with the same care and the same emphasis on active nutrient forms.
How we address an MTHFR variant
- Confirm with blood work. A gene is a tendency; homocysteine, serum folate, B12 and RBC folate tell us whether the tendency is actually showing up.
- Swap folic acid for folate. Synthetic folic acid needs MTHFR to become useful. Leafy greens, lentils, liver and methylfolate (5-MTHF) skip that step.
- Feed the cofactors. Riboflavin (B2) stabilises the enzyme. B6 and B12 keep the rest of the cycle turning.
- Start low, go slow. Some people feel jittery, irritable or headachey when methyl donors are introduced too fast. Small doses, one change at a time.
- Reduce what drains the pathway. Alcohol, smoking, some medications and chronic stress all consume methyl groups.
- Retest in 8–12 weeks. Homocysteine should move. If it doesn't, we look elsewhere in the cycle.
Folate vs folic acid
Folate is the family of B9 compounds found in food. Folic acid is the synthetic version added to fortified flour and most multivitamins. Folic acid has to be converted, step by step, into 5-MTHF before your body can use it, and MTHFR is the enzyme that performs the final step.
When MTHFR is slow, folic acid can accumulate unconverted in the blood. Unmetabolised folic acid may compete with active folate for transport and can mask a B12 deficiency on blood tests. This is why the first change for most people with a significant MTHFR variant is simply swapping the form: food folate and methylfolate in, folic acid out.
Folate-rich foods
- Leafy greens: spinach, rocket, romaine, kale
- Legumes: lentils, chickpeas, black beans
- Asparagus, broccoli, Brussels sprouts, avocado
- Liver (also rich in B12 and riboflavin)
- Eggs, for choline that supports the parallel BHMT pathway
Why "start low and go slow" matters
Methylfolate and methyl-B12 are active. Introducing them at high doses can shift neurotransmitter production quickly, and some people, particularly those with slow COMT variants, feel anxious, irritable or headachey. We start with small doses, one change at a time, and increase only once each step is comfortable.
Markers we use to track methylation
| Marker | What it tells us | Functional target* |
|---|---|---|
| Homocysteine | Overall methylation efficiency; cardiovascular signal | 6–8 µmol/L |
| Serum B12 | Circulating B12, not tissue status | upper half of range |
| Methylmalonic acid | Functional B12 status inside cells | low-normal |
| RBC folate | Longer-term folate status | mid-to-upper range |
| Serum folate | Recent intake; can be inflated by folic acid | in range, interpreted with RBC folate |
| Riboflavin (or EGRAC) | B2 status, the MTHFR cofactor | replete |
*Functional targets are narrower than laboratory reference ranges and are used to guide coaching, not to diagnose. Your physician orders and interprets blood work.
Beyond MTHFR
MTHFR gets the attention, but it is one enzyme in a cycle of many. MTR and MTRR (B12 recycling), CBS (the exit route for homocysteine), COMT (methylation of neurotransmitters and oestrogens) and PEMT (choline) all shape how much a given MTHFR variant actually matters. The methylation report reads them together.
Start with a conversation
A free 20-minute discovery call. We'll hear what's going on, tell you honestly whether genetic testing is likely to help, and outline what working together would look like.