Is A2ML1 p.Arg730His (c.2189G>A) pathogenic?

A2ML1 p.Arg730His (c.2189G>A) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.2292); Ultra-rare (popmax 0.0174%, afr); Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Arg730His (c.2189G>A)?

A2ML1 p.Arg730His (c.2189G>A) is associated with otitis media, susceptibility to, otitis media (ClinVar).

How common is A2ML1 p.Arg730His (c.2189G>A) in the general population?

A2ML1 p.Arg730His (c.2189G>A) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about A2ML1 p.Arg730His (c.2189G>A)?

AlphaMissense predicts likely benign (score 0.2292) — an in-silico prediction, not a clinical call.

A2ML1 p.Arg730His

c.2189G>A · rs200346409 · VCV626341

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2292 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.2292	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -13.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.78, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	19.92	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 0.0174% African / African-American · 13/74,790 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00814%

Overall 0.00273% 44/1,613,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,753
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,860
South Asian	0.00879%	11,372
Admixed American	0.00334%	29,951
European (non-Finnish)	0.00153%	65,541

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.Arg730His
Coding: c.2189G>A
MANE Select: NM_144670
dbSNP: rs200346409
Type: single nucleotide variant
Location: chr12:8850229 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 730: a disulfide bond; 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

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

Also linked: otitis media

Similar variants

A2ML1 p.Arg730Cys Uncertain significance ★★ same residue
A2ML1 p.Ala1445Glu 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
A2ML1 p.Gly886Val Uncertain significance ★★ ⚠ same condition
A2ML1 p.Phe672Leu 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-arg730his (accessed [today's date]).

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