Is A2ML1 p.Pro356Arg (c.1067C>G) pathogenic?

A2ML1 p.Pro356Arg (c.1067C>G) is classified Uncertain significance in A2ML1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-05-28). AlphaMissense: likely benign (0.161); Absent from gnomAD v4.1; Associated with Nonsyndromic otitis media.

What condition is associated with A2ML1 p.Pro356Arg (c.1067C>G)?

A2ML1 p.Pro356Arg (c.1067C>G) is associated with Nonsyndromic otitis media (ClinVar).

How common is A2ML1 p.Pro356Arg (c.1067C>G) in the general population?

A2ML1 p.Pro356Arg (c.1067C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about A2ML1 p.Pro356Arg (c.1067C>G)?

AlphaMissense predicts likely benign (score 0.161) — an in-silico prediction, not a clinical call.

A2ML1 p.Pro356Arg

c.1067C>G · rs863224953 · VCV217308

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.161 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nonsyndromic otitis media

Computational evidence

Protein change
AlphaMissense	0.161	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -12.19	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 2.4	GERP 0.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	23.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: A2ML1
Protein: p.Pro356Arg
Coding: c.1067C>G
MANE Select: NM_144670
dbSNP: rs863224953
Type: single nucleotide variant
Location: chr12:8839209 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 356: a UniProt-annotated variant site (risk factor for otitis media); a UniProt-annotated variant site (may be a 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.Pro356= Likely benign ★★ same residue
A2ML1 p.Pro356Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
A2ML1 p.Ala1431Val Uncertain significance ⚠ same condition
A2ML1 p.Ala810Thr Uncertain significance ⚠ same condition
A2ML1 p.Gln255Ter Uncertain significance same condition
A2ML1 p.Glu972Ter 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-pro356arg (accessed [today's date]).

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