MTHFR p.Pro492=
c.1476G>A · rs35653697 · VCV534629
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 10 submitters
gnomAD v4.1
Rare
low-frequency (popmax 3.2%, afr)
Conditions
2
Inborn genetic diseases
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -20 | GERP -2.4 |
| Overall | ||
| CADD | 2.347 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
3.2%
African / African-American · 2,403/75,078 alleles
Filtering AF
3.09%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 3.05%
Overall
0.173%
2,785/1,613,936 alleles · low-frequency
exomes 1,465/1,461,576 · genomes 1,320/152,360 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 3.2% | 31 |
| Remaining individualsnot grpmax-eligible | 0.206% | 484 |
| Admixed American | 0.16% | 625 |
| Middle Eastern | 0.149% | 673 |
| European (non-Finnish) | 0.012% | 8,368 |
| South Asian | 0.00659% | 15,179 |
| East Asian | 0.00223% | 44,878 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- MTHFR
- Protein
- p.Pro492=
- Coding
- c.1476G>A
- MANE Select
- NM_005957
- dbSNP
- rs35653697
- Type
- single nucleotide variant
- Location
- chr1:11793961 (GRCh38)
- Gene constraint
- LOEUF 0.859 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 89.13 · 4 PDB
- Residue 492
- a β-strand
Similar variants
- MTHFR p.Pro492Leu Uncertain significance ★ ⚠ same residue
- MTHFR c.1166+1G>T Likely pathogenic ★★ same condition
- MTHFR c.1166+5G>C Pathogenic/Likely pathogenic ★★ same condition
- MTHFR c.1347+1G>A Pathogenic ★★ same condition
- MTHFR c.1348-1G>C Likely pathogenic ★★ same condition
- MTHFR c.1530+1G>A Likely pathogenic ★★ same condition
- MTHFR c.1530+1G>T Likely pathogenic ★★ same condition
- MTHFR c.1632+2T>G Pathogenic/Likely pathogenic ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mthfr-p-pro492 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown