SHMT2 p.Ala331=
c.993C>T · VCV3770408
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0278%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.397 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 2.2 | GERP 1.1, phastCons 1 |
| Overall | ||
| CADD | 13.49 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0278%
South Asian · 25/89,806 alleles
Filtering AF
0.02%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0192%
Overall
0.0199%
318/1,600,122 alleles · ultra-rare
exomes 299/1,447,770 · genomes 19/152,352 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0278% | 3,592 |
| European (non-Finnish) | 0.0223% | 4,481 |
| Remaining individualsnot grpmax-eligible | 0.0194% | 5,161 |
| Admixed American | 0.0179% | 5,581 |
| Middle Eastern | 0.0167% | 5,982 |
| African / African-American | 0.0108% | 9,280 |
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
- SHMT2
- Protein
- p.Ala331=
- Coding
- c.993C>T
- MANE Select
- NM_005412
- Type
- single nucleotide variant
- Location
- chr12:57233315 (GRCh38)
- Gene constraint
- LOEUF 0.794 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 93.24 · 33 PDB
- Residue 331
- an α-helix
Similar variants
- SHMT2 p.Arg230His Uncertain significance ★★ same type
- SHMT2 p.Arg25Gln Uncertain significance ★★ ⚠ same type
- SHMT2 p.Arg359Trp Uncertain significance ★★ ⚠ same type
- SHMT2 p.Arg434Ter Uncertain significance ★★ same type
- SHMT2 p.Arg442Trp Uncertain significance ★★ ⚠ same type
- SHMT2 p.Arg488Trp Uncertain significance ★★ ⚠ same type
- SHMT2 p.Arg82Leu Uncertain significance ★★ ⚠ same type
- SHMT2 p.Asp378His 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/shmt2-p-ala331 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown