Is A2ML1 p.Ala3= (c.9T>A) pathogenic?

A2ML1 p.Ala3= (c.9T>A) is classified Benign/Likely benign in A2ML1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-12). Rare (popmax 0.557%, afr); Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Ala3= (c.9T>A)?

A2ML1 p.Ala3= (c.9T>A) is associated with otitis media, susceptibility to (ClinVar).

How common is A2ML1 p.Ala3= (c.9T>A) in the general population?

A2ML1 p.Ala3= (c.9T>A) is rare (popmax 0.557%, afr) (gnomAD).

A2ML1 p.Ala3=

c.9T>A · rs151044194 · VCV241912

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.557%, afr)

Conditions

otitis media, susceptibility to

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 0.62	GERP -0.83, phastCons 0.001
Overall
CADD	7.465	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.557% African / African-American · 418/75,066 alleles

Filtering AF 0.513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.495%

Overall 0.0292% 472/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.557%	180
Remaining individualsnot grpmax-eligible	0.0464%	2,155
Admixed American	0.035%	2,858
South Asian	0.0011%	91,072
European (non-Finnish)	0.000254%	393,329

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.Ala3=
Coding: c.9T>A
MANE Select: NM_144670
dbSNP: rs151044194
Type: single nucleotide variant
Location: chr12:8822660 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB

Full A2ML1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

otitis media, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

A2ML1 p.Ala3Thr Uncertain significance ★ ⚠ same residue
A2ML1 p.Ala1445Glu Uncertain significance ★★ ⚠ same condition
A2ML1 p.Arg730Cys Uncertain significance ★★ same condition
A2ML1 p.Arg730His Uncertain significance ★★ ⚠ same condition
A2ML1 p.Arg97Trp Uncertain significance ★★ ⚠ same condition
A2ML1 p.Asp640Asn Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gln125His Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gly777Arg 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/a2ml1-p-ala3 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown