SMAD2 p.Ser458=
c.1374C>A · rs774003411 · VCV1959963
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0357%, eas)
Conditions
1
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 1.9 | GERP -1.4, phastCons 1 |
| Overall | ||
| CADD | 7.295 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0357%
East Asian · 16/44,874 alleles
Filtering AF
0.0223%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0182%
Overall
0.000991%
16/1,613,970 alleles · ultra-rare
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
- SMAD2
- Protein
- p.Ser458=
- Coding
- c.1374C>A
- MANE Select
- NM_005901
- dbSNP
- rs774003411
- Type
- single nucleotide variant
- Location
- chr18:47841857 (GRCh38)
- Gene constraint
- LOEUF 0.249 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 78.50 · 10 PDB
- Residue 458
- a modified residue (phosphoserine); a UniProt-annotated variant site (in chtd8); the mh2 domain
Similar variants
- SMAD2 p.Ser458Thr Uncertain significance ★ ⚠ same residue
- SMAD2 p.Ala395Ser Uncertain significance ★★ ⚠ same condition
- SMAD2 p.Asn307Asp Uncertain significance ★★ ⚠ same condition
- SMAD2 p.Asn318Ser Uncertain significance ★★ ⚠ same condition
- SMAD2 p.Asn361Ser Uncertain significance ★★ ⚠ same condition
- SMAD2 p.Asn91Asp Uncertain significance ★★ ⚠ same condition
- SMAD2 p.Cys81Phe Uncertain significance ★★ ⚠ same condition
- SMAD2 p.Gln236His Uncertain significance ★★ ⚠ 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/smad2-p-ser458 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown