Is A2ML1 p.Ala810Thr (c.2428G>A) pathogenic?

A2ML1 p.Ala810Thr (c.2428G>A) is classified Uncertain significance in A2ML1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-05-28). AlphaMissense: likely benign (0.2168); Very rare (popmax 8.47e-05%, nfe); Associated with Nonsyndromic otitis media.

What condition is associated with A2ML1 p.Ala810Thr (c.2428G>A)?

A2ML1 p.Ala810Thr (c.2428G>A) is associated with Nonsyndromic otitis media (ClinVar).

How common is A2ML1 p.Ala810Thr (c.2428G>A) in the general population?

A2ML1 p.Ala810Thr (c.2428G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about A2ML1 p.Ala810Thr (c.2428G>A)?

AlphaMissense predicts likely benign (score 0.2168) — an in-silico prediction, not a clinical call.

A2ML1 p.Ala810Thr

c.2428G>A · rs863224954 · VCV217309

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Nonsyndromic otitis media

Computational evidence

Protein change
AlphaMissense	0.2168	likely benign
REVEL	0.332	indeterminate
SaProt	LLR -10.43	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.84e-05% 1/1,461,882 alleles · very 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: A2ML1
Protein: p.Ala810Thr
Coding: c.2428G>A
MANE Select: NM_144670
dbSNP: rs863224954
Type: single nucleotide variant
Location: chr12:8851977 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 810: a β-strand; a UniProt-annotated variant site (risk factor for otitis media)

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

Disease context

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

Similar variants

A2ML1 p.Ala810Asp Uncertain significance ★★ ⚠ same residue
A2ML1 p.Ala810= Likely benign ★★ same residue
A2ML1 p.Ala1431Val Uncertain significance ⚠ same condition
A2ML1 p.Gln255Ter Uncertain significance same condition
A2ML1 p.Glu972Ter Uncertain significance same condition
A2ML1 p.Pro356Arg Uncertain significance ⚠ same condition
A2ML1 c.1834-1G>T Uncertain significance ★★ same type
A2ML1 c.3264+4C>T 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-ala810thr (accessed [today's date]).

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