MTHFD1 p.Ser323=
c.969A>C · rs200168500 · VCV2781590
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.018%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · A>T here scores Δ0.23 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.3 | GERP -1.6, phastCons 0.42 |
| Overall | ||
| CADD | 10.98 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.018%
Middle Eastern · 1/5,562 alleles
Filtering AF
6.8e-05%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.9e-05%
Overall
0.000248%
4/1,613,564 alleles · ultra-rare
exomes 3/1,461,280 · genomes 1/152,284 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.018% | 5,562 |
| European (non-Finnish) | 0.000254% | 393,340 |
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.Ser323=
- Coding
- c.969A>C
- MANE Select
- NM_005956
- dbSNP
- rs200168500
- Type
- single nucleotide variant
- Location
- chr14:64426034 (GRCh38)
- Gene constraint
- LOEUF 0.51 · pLI 0.83 (gnomAD)
- Structure
- AlphaFold pLDDT 94.63 · 12 PDB
- Residue 323
- a UniProt-annotated variant site (in cimah); the 'formyltetrahydrofolate synthetase domain' region
Similar variants
- 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
- MTHFD1 p.Arg293Cys 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-ser323 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown