MTHFR A1298C: Folate Metabolism and Your Genotype

5 days ago

3 min read

MTHFR A1298C, also called rs1801131, is a common genetic variant that can reduce the activity of an enzyme involved in folate metabolism. It receives less attention than MTHFR C677T, but it offers another useful piece of the picture.

One early study found that people carrying two A1298C variant copies had approximately 60% of the comparison group’s MTHFR activity in lymphocytes, a type of white blood cell. That is a measurable biochemical difference—but it does not mean their bodies performed all methylation reactions at 60% capacity [R].

The interesting distinction is that lower enzyme activity does not necessarily translate into elevated homocysteine or low blood folate, particularly when A1298C occurs on its own.

You can explore this marker alongside MTHFR C677T in the free GenesUnveiled Methylation Panel.

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What Does MTHFR Do?

The MTHFR gene produces methylenetetrahydrofolate reductase, an enzyme that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, often shortened to 5-MTHF. This folate form helps support the conversion of homocysteine into methionine. Methionine is used to make proteins and other important compounds [R].

MTHFR therefore helps supply a particular folate form needed for homocysteine recycling. Differences in its activity can influence this pathway, but the significance depends on the variant and the wider biological context.

What Is MTHFR A1298C?

A1298C changes one amino acid in the MTHFR protein: glutamate becomes alanine at position 429. You may also see it called Glu429Ala or E429A. The familiar A1298C name uses the gene’s coding-strand notation. In forward-strand raw DNA data, rs1801131 is represented using T and G [R].

Forward-strand genotype	Interpretation
TT	No copies of the A1298C variant; other MTHFR variants may still be present.
TG	One variant copy; reduced enzyme activity has been observed in cell studies.
GG	Two variant copies; generally a greater reduction in measured activity than with one copy.

The direction of the activity difference was demonstrated in early research, with a more pronounced reduction in people carrying two variant copies [R].

How Much Does A1298C Reduce Enzyme Activity?

Researchers have measured the effect using different methods.

A 1998 study reported approximately 60% of control activity in lymphocytes among people with two A1298C variant copies [R].

A 2001 laboratory study expressed the human enzyme in bacteria. The A1298C version retained approximately 68% of reference activity, compared with 45% for the C677T version under the same experimental conditions. A1298C also did not produce the increased heat sensitivity seen with C677T [R].

These findings establish a functional effect. However, the percentages describe particular experiments. They are not a direct measurement of your whole-body folate processing.

Does A1298C Raise Homocysteine?

A1298C alone has not consistently been associated with elevated homocysteine.

In the original Dutch study, neither one nor two A1298C variant copies were associated with higher plasma homocysteine or lower plasma folate, despite the reduction in enzyme activity [R].

The CDC also states that evidence is insufficient to show that A1298C alone significantly affects how the body processes folate [R].

What If You Also Carry MTHFR C677T?

The combination deserves more attention than A1298C in isolation.

In a study examining 198 participants from the NHLBI Family Heart Study, people heterozygous for both variants had higher fasting homocysteine than people carrying only one C677T variant copy [R].

Using forward-strand notation, one copy of each appears as:

rs1801133: AG — one C677T variant copy.
rs1801131: TG — one A1298C variant copy.

This combination is often discussed as compound heterozygosity, although ordinary raw DNA results generally do not establish whether the variants sit on opposite gene copies.

The practical value is in considering both markers together. Read our MTHFR C677T guide for the other part of that comparison.

Does A1298C Mean You Need Methylfolate?

Your genotype alone does not establish a need for methylfolate or determine a supplement dose.

People with common MTHFR variants can process folic acid. The CDC advises that these variants are not a reason to avoid it and emphasizes the importance of folate intake when determining blood folate levels [R].

If you could become pregnant, the CDC recommends 400 micrograms of folic acid daily, including when an MTHFR variant is present. Individual medical circumstances may require different guidance [R].

Explore Your MTHFR A1298C Result for Free

The free GenesUnveiled Methylation Panel checks MTHFR A1298C and C677T, together with selected markers in MTRR, MTR, TCN2, COMT, and MTHFD1.

Your raw DNA file is processed in your browser. Your raw file and individual genetic results are not uploaded to our servers during analysis. Coverage varies between testing providers, so a missing marker means its genotype could not be determined from your file.