MTHFR rs115366802: Understanding the p.Gln387Ter Variant
rs115366802 is an extremely rare nonsense variant located in the MTHFR gene, resulting in a premature termination signal known as p.Gln387Ter. While common MTHFR variants such as C677T mildly reduce enzyme efficiency, rs115366802 introduces a stop codon that truncates the protein and leads to severe loss of methylenetetrahydrofolate reductase function. In autosomal recessive states—such as homozygosity or compound heterozygosity with another deleterious mutation—it is associated with severe inborn errors of folate metabolism and homocystinuria.
What each genotype means
Typical MTHFR gene function
This genotype represents the most common form of the MTHFR gene, where both copies do not carry the specific p.Gln387Ter nonsense mutation. Individuals with this genotype are not expected to have the severe MTHFR deficiency associated with this specific variant.
This is the most common genotype, found in the vast majority of the global population.
Carrier of rare variant
This genotype indicates that one copy of the MTHFR gene contains the p.Gln387Ter nonsense mutation. Because this condition is typically inherited in a recessive manner, carriers generally do not exhibit the severe symptoms of MTHFR deficiency, though they may pass the variant to their offspring.
This genotype is extremely rare, with the variant allele frequency reported at less than 0.0001 in general population databases.
Potential MTHFR deficiency
This genotype indicates that both copies of the MTHFR gene carry the p.Gln387Ter nonsense mutation, which is associated with severe MTHFR deficiency and homocystinuria. Individuals with this result should consult with a medical geneticist or healthcare provider to discuss clinical implications and appropriate management.
This genotype is exceptionally rare in the general population.
What Is rs115366802 and Where Is It Located?
rs115366802 is a single-nucleotide variant residing within the MTHFR gene on chromosome 1. Unlike benign or mild missense polymorphisms, this change introduces a premature stop signal (p.Gln387Ter, historically annotated as Q387X). In the genetic code, this nonsense change instructs cellular machinery to halt protein translation early, resulting in a truncated, nonfunctional methylenetetrahydrofolate reductase polypeptide or nonsense-mediated mRNA decay. While common population polymorphisms in MTHFR simply alter single amino acids and slightly decrease enzymatic efficiency, truncating mutations like rs115366802 represent severe structural interruptions in the coding sequence.
The Biological Function of the MTHFR Gene
The MTHFR gene encodes the enzyme methylenetetrahydrofolate reductase, a vital catalyst in human one-carbon and folate metabolism. This enzyme is responsible for converting 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (5-MTHF). The primary product, 5-MTHF, is the essential methyl donor needed by methionine synthase to remethylate homocysteine into methionine. When functional MTHFR is profoundly deficient, homocysteine cannot be effectively recycled via the folate pathway. This biochemical bottleneck leads to severe accumulation of homocysteine in the blood and tissues alongside a systemic deficit in methionine and downstream methyl donors.
Clinical Significance and Strength of Evidence
The clinical evidence linking severe loss-of-function MTHFR mutations to inborn errors of metabolism is established, though individual documentation for rs115366802 specifically remains limited due to extreme population rarity. In classic metabolic genetics, biallelic mutations in MTHFR cause severe MTHFR deficiency and homocystinuria. Unlike common functional variants associated with mild vascular or nutritional traits, recessive phenotypes here can present in infancy or childhood with developmental delays, microcephaly, seizures, and progressive neurological impairment. Individuals carrying only a single copy (heterozygotes) typically retain sufficient residual enzymatic activity to remain asymptomatic under standard metabolic conditions.
Population Frequency and Genetic Rarity
A critical distinction in genomic medicine is the separation between common polymorphic variants and rare pathogenic mutations. Common variants in MTHFR, such as C677T and A1298C, are carried by a substantial percentage of the global population. In stark contrast, rs115366802 is exceptionally rare across all ancestries. High-throughput reference databases like the Genome Aggregation Database (gnomAD) indicate a minor allele frequency (MAF) well below 0.0001. As a consequence, finding an individual who carries even one copy of rs115366802 is an unusual finding, and homozygous individuals are extraordinarily rare.
What Readers Can and Cannot Conclude
Direct-to-consumer genetic screening arrays occasionally flag rare variants, but raw genotype calls for low-frequency changes carry a notable rate of technical false positives. Finding this variant on an unvalidated raw data file should never be taken as a medical diagnosis. Furthermore, carrier status (having one copy) does not cause severe homocystinuria, as the condition follows an autosomal recessive pattern requiring two dysfunctional alleles. Anyone reviewing unexpected genetic findings or concerned about metabolic disorders should seek clinical confirmation via Sanger sequencing and consultation with a board-certified geneticist or genetic counselor.
How common is this variant?
rs115366802 is exceptionally rare worldwide, with an overall minor allele frequency (MAF) of less than 0.0001 in large population datasets like gnomAD, and homozygous states are virtually absent outside of rare clinical presentations.
Frequently asked questions
Is rs115366802 the same as the common MTHFR C677T variant?
No, rs115366802 is completely different from common polymorphisms like C677T (rs1801133) or A1298C (rs1801131). While the common variants alter a single amino acid and slightly reduce enzyme efficiency, rs115366802 is a rare nonsense mutation (p.Gln387Ter) that halts protein production early, causing severe loss of function.
Does having one copy of rs115366802 cause severe homocystinuria?
Typically, no. MTHFR deficiency resulting in severe homocystinuria is inherited in an autosomal recessive manner, meaning both copies of the gene must carry a disruptive variant to produce clinical disease. Individuals with only one altered copy are usually asymptomatic carriers because their remaining functional copy produces adequate enzyme.
How common is rs115366802 in the general public?
This variant is vanishingly rare in the general population. Large-scale genomic sequencing projects like gnomAD demonstrate that the variant allele occurs at a frequency of less than 1 in 10,000 individuals across global ancestries.
What should I do if my direct-to-consumer DNA file shows rs115366802?
Do not panic or self-prescribe supplements or medications based on raw genomic data files. Rare variant calls on consumer genotyping arrays are often laboratory artifacts or false positives. You should review the result with a healthcare professional or genetic counselor, who can arrange standard clinical sequencing to verify the finding.
Sources & further reading
Educational information only, last refreshed 9/8/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Variant in the MTHFR locus frequently studied in association with folate metabolism and homocysteine levels.
MTHFR missense variant (c.1793G>A, p.Arg594Gln) commonly evaluated alongside canonical variants for folate metabolism and hyperhomocysteinemia predisposition.
Functional polymorphism influencing homocysteine dynamics and vascular endothelial recovery during high-intensity training.
Common variant (C677T) influencing folate metabolism and plasma homocysteine levels.
The C677T variant in the MTHFR gene is associated with reduced enzyme activity and mild hyperhomocysteinemia, particularly in individuals with low folate intake.
The MTHFR 677C>T (Ala222Val) variant encodes a thermolabile enzyme with reduced activity. While associated with elevated homocysteine levels in the presence of low folate, major professional guidelines (e.g., ACMG) advise against routine clinical testing for cardiovascular or thrombophilia risk due to lack of clinical utility.