MTHFD1 rs2236225: Choline, Folate, and Your Genotype
MTHFD1 rs2236225 connects two nutrients that are often discussed separately: folate and choline.
The MTHFD1 enzyme helps process folate-derived one-carbon units. That is small chemical building blocks used in DNA production and connected metabolic pathways. A common variant, also called G1958A, changes the enzyme’s structure and has been investigated for its effects on stability and cellular metabolism [R].
Its nutritional relevance became particularly interesting when a controlled feeding study found that carriers were more susceptible to signs of deficiency during a very low-choline diet [R].
You can explore rs2236225 in the free GenesUnveiled Methylation Panel.
Quick Answer: What Does MTHFD1 rs2236225 Mean?
Rs2236225 changes one amino acid in MTHFD1:
G encodes arginine, abbreviated Arg or R.
A encodes glutamine, abbreviated Gln or Q.
The variant is therefore also called Arg653Gln, R653Q, or G1958A [R]
Research supports differences in enzyme stability and suggests that carrying A can influence susceptibility to choline depletion under particular dietary conditions. Your genotype does not directly measure your current folate level, choline status, or methylation activity.
What Does the MTHFD1 Gene Do?
MTHFD1 produces a trifunctional enzyme: one protein carrying out three related enzymatic activities.
Together, these activities help interconvert forms of tetrahydrofolate, allowing folate-derived one-carbon units to be used for different metabolic purposes. One important function is supporting purine synthesis, the production of building blocks used in DNA and RNA [R].
This places MTHFD1 within one-carbon metabolism, the connected network through which folate, choline, and other nutrients contribute to cellular chemistry.
MTHFD1 and MTHFR have related names but different jobs. For the MTHFR side of the pathway, read our MTHFR rs1801133 explanation.
What Did Functional Experiments Find?
Researchers compared the Arg653 and Gln653 forms in laboratory experiments.
The Gln653 enzyme had:
A 36% shorter half-life at 42°C, indicating reduced stability under the experimental heat conditions.
Approximately 26% lower incorporation of formate into DNA in a modified mouse-cell system expressing the variant protein.
Its affinity for the tested substrates remained normal [R].
These findings support a functional effect, but the measurements need their context. They do not mean that AA individuals produce 26% less DNA or have a fixed 36% reduction in methylation.
GG, AG, and AA: What Do Your Results Mean?
Genotype | Protein forms | Interpretation |
GG | Arg/Arg | Two copies encoding arginine at position 653. |
AG | Arg/Gln | One copy encoding each form. |
AA | Gln/Gln | Two copies encoding the Gln653 form investigated in functional studies. |
In the choline-depletion study discussed below, AG and AA were grouped together for the main carrier comparison. That result does not establish that AA has twice the effect of AG.
MTHFD1 and Choline Deficiency: The Sevenfold Finding
A 2005 controlled feeding study involving 54 adults examined whether folate-pathway variants influenced susceptibility to choline deficiency. Participants consumed a very low-choline diet under supervision. Researchers assessed changes such as increased liver fat or elevated creatine kinase, a marker of muscle injury, that resolved after choline was restored.
Signs of deficiency occurred in approximately:
Genotype group | Participants showing deficiency signs |
GG | 40% |
AG and AA combined | 82% |
The reported odds ratio was 7.0, with a 95% confidence interval of 2.0–25 [R].
That means sevenfold higher odds under the depletion conditions, not seven times the daily choline requirement. The observed percentages were roughly twofold apart; odds and probabilities are different measures.
The small sample and wide confidence interval limit precision. Nevertheless, the study provides direct human evidence that inherited variation can influence how people respond to a restricted nutrient supply.
Why Would a Folate Gene Affect Choline Needs?
Folate and choline share some metabolic responsibilities. Choline can be converted into betaine, which supplies methyl groups for one route of homocysteine remethylation. Choline is also needed to make phosphatidylcholine, an important component of cell membranes and lipid transport. When folate availability is limited, reliance on choline-derived methyl groups can increase [R].
This creates a biological connection between folate handling and the amount of choline available for other functions. It helps explain why researchers study MTHFD1 alongside choline metabolism rather than treating each nutrient pathway independently.
Does Folate Intake Change the Result?
A 2009 controlled feeding study followed 43 premenopausal Mexican American women through seven weeks of folate restriction and seven weeks of folate treatment. Choline intake remained constant.
During restriction, AA showed a trend toward a less favorable homocysteine result compared with GG, but this did not reach conventional statistical significance: P = 0.085.
During folate treatment, researchers detected no genotype effects on the responses of the measured variables [R].
Does the A Allele Mean You Need Choline Supplements?
The genotype alone cannot determine a supplement dose. The strongest human finding concerns susceptibility during deliberate choline restriction, rather than a validated daily requirement for each genotype. A practical starting point is understanding your existing dietary intake. Choline occurs in foods including eggs, meat, fish, dairy products, soybeans, and some beans and vegetables [R].
An AG or AA result provides a reason to pay attention to choline alongside folate. It does not establish a deficiency or show that you need high-dose supplements.
GG also does not guarantee protection from an inadequate diet.
What Your MTHFD1 Result Means for You
Rs2236225 is useful because its evidence connects a protein change, laboratory findings, and a controlled human nutrition study.
The clearest interpretation is:
GG: carries the Arg653 form used as the comparison in the cited studies.
AG or AA: carries the Gln653 form associated with altered stability and greater susceptibility to choline depletion in the small feeding study.
All genotypes: require interpretation alongside diet and the conditions studied.
Your result offers context for nutrient metabolism. It does not reveal how much choline is currently reaching your tissues or whether your methylation pathways are functioning adequately.
Explore Your MTHFD1 Result in the Free Methylation Panel
MTHFD1 illustrates how a folate-processing gene can influence the body’s response to another nutrient. Its connection with choline makes it a useful addition to understanding methylation-related pathways beyond MTHFR alone.
Visit the free Methylation Panel to explore MTHFD1 alongside MTHFR, MTRR, MTR, TCN2, and COMT. You can analyze your existing raw DNA file in your browser to check which results are available.
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