To Health With That!

Schedule a free 15 minute consult now
Follow us :

C677T Mutations – What You Need To Know

In the current state of medical research, studies don’t often differentiate between C677T mutations and A1298C mutations so lots of the research applies to both – lumping MTHFR polymorphisms into one category, and “wild-type” genes (the research term for “normal”) into another. Still, we are starting to get a few more specific pieces of information. Let’s go over the technical details first.

C677T Nomenclature

  • 677 is the marker for this particular MTHFR gene.
  • The official genetics labeling of this gene is Rs1801133.
  • The C…T stand for the nucleotide bases you actually have. C = cytosine, T = thymine. Essentially C677T means At location 677 there is typically a cytosine (C) but there is actually thymine (T).
  • The “wild-type” or typical form of this gene is C677C.
  • You have two possible copies – one from each parent.
  • Two wild-type copies = typical genetics. No polymorphism. (C677C)
  • One wild-type and one altered (bad) copy = heterozygous. (C677T)
  • Two altered (bad) copies = homozygous. (this is sometimes just written as C677T and sometimes as 677TT. Occasionally I see T677T, but that tends to be confusing.)
  • The C677T polymorphism results in an amino acid substitution in the final protein of the MTHFR enzyme. This is an ala222-to-val (A222V) substitution. This means in the MTHFR enzyme that the gene manufactures, there is supposed to be an alanine, but instead, we see a valine.
  • This substitution happens in the part of the enzyme that is presumed to be the catalytic region.
 MTHFR C677T mutation
C677T Mutations – What You Need To Know

So… What Does That Mean?

We can sum it up pretty simply.

T;T individuals (homozygous) have about 30% of the expected activity of the enzyme. This means ~ 60% compromise.

C;T folks (heterozygous) have about 65% of the expected activity of the enzyme. Meaning ~28% compromise.

It is really important to notice that both of these groups have some enzyme activity – this copy of the MTHFR enzyme is still working, it’s just got a lower capacity because the enzyme “magic chair” is lumpy. If you have no idea what I’m talking about, follow the link to see the simplest possible description of what enzymes do.

The different levels of compromise between MTHFR C677T mutations - heterozygous and homozygous.
The different levels of compromise between MTHFR C677T mutations – heterozygous and homozygous.

Is This Mutation Worse Than Other Mutations?

Honestly, the biggest difference that we know of between the C677T and the A1298C mutation is just the level of enzyme compromise. Because this particular polymorphism is associated with a bigger compromise, more research has been done on this polymorphism. The research does indicate that this mutation has more serious effects, but logically that is likely due to the level of compromise.

What that means is that independent of the degree to which it slows down the enzyme, there isn’t really any difference between C677T and A1298C that we know of. Of course, more research might reveal something, but at this time the degree of compromise in the enzyme activity seems to be the strongest determinant of how much you are affected.

But Amy – That Isn’t What The Internets Say!

I know. I have seen every kind of article claiming that A1298C mutations have more tendency towards neurotransmitter imbalance than C677T, Also, that C677T mutations are more likely to lead to high homocysteine. But as far as I can tell, this started with someone making some kind of conclusion, and then the rest of the internet echoing that same conclusion back to them without bothering to actually do the research.

As far as all of the research I have seen, the thing that matters is how compromised your MTHFR enzyme is, in combination with how much folate you’re getting. As more research is completed this idea might be refined, revised, or even overturned completely, but for now, this is it.

Of course, someone might have a compelling argument why I’m wrong and honestly, I would love to hear it, and even more, I”d love to see the research!

Just for convenience, here is a table with levels of compromise.

Mutation% Enzyme Activity
(Presented as a range because different studies find different values.)
C677T51 – 73%
C677TT22 – 32%
A1298C60 – 92%
A1298CC52 – 60%
Compound heterozygous.~36 – 60%

It’s kind of fascinating, actually, that we speak with such conviction about things like level of compromise, when in reality there are very few studies, and those studies don’t actually agree with each other. The three that were used for the above ranges are linked below, just in case you’re curious. You will note that the difference between a 36% activity and a 60% activity is almost a factor of two, and yet between two different studies, the range was that broad. So obviously, the research has a long way to go.

To Clarify – There Probably Are Differences Between C677T and A1298C – We Just Don’t Understand Them Yet.

Because we’re in the early phase of research, the bulk of studies look at wild-type genes vs. polymorphisms as a group and then sometimes pull out smaller data like homozygous vs. heterozygous and detail things like that. Once we’ve built up a more complete body of research, then the smaller questions will start to be explored. I strongly suspect that we will find differences in the challenges faced by both groups and I also suspect that they won’t be nearly so cut and dry as “this group has homocysteine challenges where the other group has a hard time making neurotransmitters.” My suspicion is more along the lines of differences in response to therapeutic interventions and treatments.

C677T versus A1298C is a better indicator of overmethylation vs. undermethylation than C677T versus undermethylation
C677T versus A1298C is a better indicator of overmethylation vs. undermethylation than C677T versus undermethylation

Clinically, The Overmethylation vs. Undermethylation Distinction Is Far More Useful Than The Particular Mutation.

The basic state differences actually tell us likely responses to supplements, while the particular mutation does no such thing so clinically it is far more relevant than the particular genetic issue. The one thing that knowing your genetics does tell us, is the actual level of compromise, which can be important (but can also usually be extrapolated from symptoms).

This is part of why I don’t think genetic testing is necessary for all people who suspect they have an MTHFR issue. At the end of the day, the symptoms that you experience are far more telling than the actual polymorphisms.

Share with friends:

MTHFR is a common genetic mutation that can contribute to anxiety, depression, fatigue, chronic pain, infertility, and more serious conditions like breast implant illness, heart attack, stroke, chronic fatigue syndrome, and some types of cancer. If you know or suspect you have an MTHFR variant, schedule a free 15-minute meet-and-greet appointment with MTHFR expert Dr. Amy today.

Book Your Appointment
Amy Neuzil
Amy Neuzil

Dr. Amy Neuzil, N.D. is a leading expert in MTHFR and epigenetics, and she is passionate about helping people achieve optimal health and wellness for their genetic picture. She has helped thousands of people overcome health challenges using a simple, step-by-step approach that starts with where they are today. Dr. Neuzil's unique approach to wellness has helped countless people improve their energy levels, lose weight, and feel better mentally and emotionally. If you're looking for a way to feel your best, Dr. Amy Neuzil can help. Contact her today to learn more about how she can help you achieve optimal health and wellness.

Articles: 183


  1. Thank you so much for sharing all of this information! I found out my son has homozygous for the T allele of the C677T polymorphism in the MTHFR gene back in August. He took a GeneSight test due to the fact he was (and is) struggling severely with anxiety and depression. I asked about this several times and the doctor just said he needed a supplement and to ask his pharmacist. The pharmacist gave him a folic acid supplement. Thus, in addition to the food he was eating, his multi vitamin and the folic acid supplement, not to mention the nine different anti-depression meds he was on-he was basically being poisoned! By chance three weeks ago at a follow up, I again brought up the folic acid thing. The doctor then told me about removing folic acid from my son’s diet, changing his multi vitamin etc… I told him what the pharmacist said and he said “isn’t that sad that he does not know about this…”. In any case, I have been all over your wonderful site and have been working hard to clean up my son’s diet, environment, and personal care products. I have two questions. His doctor recommended Mary Ruth’s Liquid Morning Vitamin. Is this good for him? Second, I’m assuming since he was on a folic acid supplement for five months, he must have a major “back log” or “to do list”. How many weeks before he starts to feel better?
    I have also asked my son’s doctor for a genetic doctor to help my son take the next step of adding methylfolate to his diet. Thank you again for this amazing resource of information!

    • Hi Tamara,
      I am so glad you found the site and so sorry to hear about the folic acid recommendation from the pharmacist. I’m really impressed that your doctor was actually aware that folic acid is a problem for people with MTHFR – that’s a really great sign. The Mary Ruth’s is great – it seems to be high quality and easy to take. There will be a back log, partly because of the folic acid, partly because of the anti-depressant medications, and just partly from being alive on this earth for some years. It’s hard to say how long it will take for him to notice a difference. Some people seem to notice almost right away, and for some people we really have to find the right dose before they notice a big shift. Thanks for being here!

Leave a Reply

Your email address will not be published. Required fields are marked *