MTHFD1 p.Ser92=
c.276T>G · rs371016333 · VCV1586366
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.0062%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.36 | GERP -1 |
| Overall | ||
| CADD | 8.959 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0062%
European (non-Finnish) · 73/1,177,114 alleles
Filtering AF
0.00504%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00464%
Overall
0.00478%
77/1,610,918 alleles · very rare
exomes 72/1,458,674 · genomes 5/152,244 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0062% | 16,125 |
| Remaining individualsnot grpmax-eligible | 0.00481% | 20,801 |
| Admixed American | 0.00167% | 59,996 |
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
- MTHFD1
- Protein
- p.Ser92=
- Coding
- c.276T>G
- MANE Select
- NM_005956
- dbSNP
- rs371016333
- Type
- single nucleotide variant
- Location
- chr14:64415393 (GRCh38)
- Gene constraint
- LOEUF 0.51 · pLI 0.83 (gnomAD)
- Structure
- AlphaFold pLDDT 94.63 · 12 PDB
- Residue 92
- the 'methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (d/c) domain' region
Similar variants
- MTHFD1 p.Ser92Tyr Uncertain significance ★ ⚠ same residue
- MTHFD1 c.727+1G>A Pathogenic/Likely pathogenic ★★ same type
- MTHFD1 p.Arg173Cys Pathogenic/Likely pathogenic ★★ same type
- MTHFD1 p.Gln100Ter Likely pathogenic ★★ same type
- MTHFD1 p.Glu225Ter Pathogenic ★★ same type
- MTHFD1 p.Ser49Phe Pathogenic/Likely pathogenic ★★ same type
- MTHFD1 c.186+5C>T Uncertain significance ★★ same type
- MTHFD1 p.Arg173His Uncertain significance ★★ ⚠ same type
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/mthfd1-p-ser92 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown