A2ML1 p.Leu493=
c.1477T>C · rs200088686 · VCV413820
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 9 submitters
gnomAD v4.1
Rare
rare (popmax 0.825%, mid)
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 -0.84, phastCons 1 |
| Overall | ||
| CADD | 9.969 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.825%
Middle Eastern · 50/6,062 alleles
Filtering AF
0.643%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.578%
Overall
0.0124%
200/1,614,070 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.825% | 121 |
| Admixed American | 0.0516% | 1,936 |
| Remaining individualsnot grpmax-eligible | 0.0192% | 5,209 |
| European (non-Finnish) | 0.00873% | 11,456 |
| African / African-American | 0.00267% | 37,515 |
| South Asian | 0.0022% | 45,543 |
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.Leu493=
- Coding
- c.1477T>C
- MANE Select
- NM_144670
- dbSNP
- rs200088686
- Type
- single nucleotide variant
- Location
- chr12:8845442 (GRCh38)
- Gene constraint
- LOEUF 0.953 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 80.61 · 5 PDB
- Residue 493
- a disulfide bond; a UniProt-annotated variant site (risk factor for otitis media); a β-strand
Similar variants
- A2ML1 p.Leu493Ser 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-leu493 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown