A2ML1 p.Ser406=
c.1218C>T · rs747023059 · VCV696685
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0869%, eas)
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 -2.8 | GERP -2.9 |
| Overall | ||
| CADD | 1.718 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0869%
East Asian · 39/44,886 alleles
Filtering AF
0.0653%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0578%
Overall
0.007%
113/1,613,894 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.0869% | 1,151 |
| South Asian | 0.0143% | 7,005 |
| Remaining individualsnot grpmax-eligible | 0.0064% | 15,622 |
| European (non-Finnish) | 0.00466% | 21,454 |
| Admixed American | 0.00167% | 59,982 |
| African / African-American | 0.00134% | 74,874 |
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
- A2ML1
- Protein
- p.Ser406=
- Coding
- c.1218C>T
- MANE Select
- NM_144670
- dbSNP
- rs747023059
- Type
- single nucleotide variant
- Location
- chr12:8841506 (GRCh38)
- Gene constraint
- LOEUF 0.953 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 80.61 · 5 PDB
- Residue 406
- a UniProt-annotated variant site (risk factor for otitis media); a β-strand
Similar variants
- A2ML1 p.Ser406Ala Uncertain significance ★ ⚠ same residue
- A2ML1 c.1834-1G>T Uncertain significance ★★ same type
- A2ML1 c.3264+4C>T Uncertain significance ★★ same type
- A2ML1 c.3933+4A>G Uncertain significance ★★ same type
- A2ML1 c.409+1G>A Uncertain significance ★★ same type
- A2ML1 c.4221+2T>C Uncertain significance ★★ same type
- A2ML1 c.*1+1G>A Uncertain significance ★★ same type
- A2ML1 p.Ala1002Val 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/a2ml1-p-ser406 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown