Is A2ML1 p.Arg730Cys (c.2188C>T) pathogenic?

A2ML1 p.Arg730Cys (c.2188C>T) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-26). AlphaMissense: ambiguous (0.3654); Very rare (popmax 0.0066%, sas); Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Arg730Cys (c.2188C>T)?

A2ML1 p.Arg730Cys (c.2188C>T) is associated with otitis media, susceptibility to (ClinVar).

How common is A2ML1 p.Arg730Cys (c.2188C>T) in the general population?

A2ML1 p.Arg730Cys (c.2188C>T) is very rare (popmax 0.0066%, sas) (gnomAD).

What do computational predictors say about A2ML1 p.Arg730Cys (c.2188C>T)?

AlphaMissense predicts ambiguous (score 0.3654) — an in-silico prediction, not a clinical call.

A2ML1 p.Arg730Cys

c.2188C>T · rs753349449 · VCV1464079

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0066%, sas)

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.3654	ambiguous
REVEL	0.395	indeterminate
SaProt	LLR -15.75	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP 1.7, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	25.1	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 0.0066% South Asian · 6/90,968 alleles

Filtering AF 0.00287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.0018% 29/1,613,290 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,862
South Asiangrpmax	0.0066%	15,161
African / African-American	0.004%	24,983
East Asian	0.00223%	44,806
Admixed American	0.00167%	59,920
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00119%	84,269

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg730Cys
Coding: c.2188C>T
MANE Select: NM_144670
dbSNP: rs753349449
Type: single nucleotide variant
Location: chr12:8850228 (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

Similar variants

A2ML1 p.Arg730His 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-arg730cys (accessed [today's date]).

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