What does MTHFR actually mean?
A thread through the evidence — ClinVar, gnomAD, ClinGen, and GTEx.
Data at a glance
Quantitative view across ClinVar, gnomAD, GTEx, and ClinGen.
GTEx is featured first. Use the selector to move across data sources.
GTEx top tissue expression
Median TPM across top tissues.
ClinVar classification mix
1,034 submitted variants for this gene.
Radial view shows each category as a percent of total submitted variants (1,034). ClinVar categories can overlap, so row percentages may sum above 100%.
Pathogenic
299 (29%)Likely pathogenic
0 (0%)VUS
426 (41%)Likely benign
0 (0%)Benign
0 (0%)Conflicting
0 (0%)Other / unclassified
309 (30%)299
Pathogenic + likely
426
VUS
309
Other / unclassified
gnomAD profile
Constraint metrics plus full-gene variant distribution across GRCh38 coordinates.
pLI0.00
Higher suggests stronger LoF intolerance
LOEUF0.917
Lower indicates stronger LoF constraint
Mis-Z1.83
Higher can suggest missense depletion
Genome-mapped variant landscape
3,610 shown
This is a positional map of gnomAD population variation, not a pathogenicity map. For pathogenic vs VUS, use the ClinVar panel.
chr1:11,785,723-11,806,455 on GRCh38
Display: All gnomAD variants. Click a bar to inspect that genomic interval.
Binned from the full gene variant set to preserve complete counts while keeping UI readable.
ClinGen gene-disease validity
Evidence strength assigned by ClinGen curation.
Definitive
Evidence strength100%
Variation
MTHFR has 1,034 variants submitted to ClinVar (chromosome 1). Among them, 299 are classified as pathogenic or likely pathogenic, and 426 remain Variants of Uncertain Significance. Each variant is a thread in the story — some we understand, many we're still learning.
Interpretation
Here's the uncomfortable truth: 41% of MTHFR variants in ClinVar are classified as "Uncertain Significance" (VUS). That means the labs that sequenced them couldn't confidently say whether they're harmful or harmless. This isn't a failure — it's an honest reflection of where the science stands. Interpretations change as evidence accumulates.
Constraint
gnomAD's constraint metrics tell us how tolerant MTHFR is to different types of mutations in the general population. A LOEUF score of 0.92 suggests moderate tolerance. This is indirect evidence, but it's powerful: evolution has been running this experiment for millions of years.
Expression
GTEx data shows where MTHFR is most active in the body. Top tissues: Ovary (26.7 TPM), Nerve Tibial (25.2 TPM), Spleen (23.5 TPM). Where a gene is expressed often aligns with where pathogenic variants cause disease — though the gene isn't silent elsewhere; it may play roles across many cell types.
Meaning
So what does it all mean? MTHFR is a gene we're still learning about. 299 variants are classified as pathogenic or likely pathogenic — evidence that's strong and actionable when it applies to you. 426 variants remain uncertain. That's the honest state of genomic medicine: if you carry a pathogenic MTHFR variant, the evidence speaks clearly. If you carry a VUS, the evidence is still accumulating. Either way, you deserve to understand what the science actually says.