Is A2ML1 p.Met649Val (c.1945A>G) pathogenic?

A2ML1 p.Met649Val (c.1945A>G) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-30). AlphaMissense: likely benign (0.051); Ultra-rare (popmax 0.0307%, afr); Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Met649Val (c.1945A>G)?

A2ML1 p.Met649Val (c.1945A>G) is associated with otitis media, susceptibility to (ClinVar).

How common is A2ML1 p.Met649Val (c.1945A>G) in the general population?

A2ML1 p.Met649Val (c.1945A>G) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about A2ML1 p.Met649Val (c.1945A>G)?

AlphaMissense predicts likely benign (score 0.051) — an in-silico prediction, not a clinical call.

A2ML1 p.Met649Val

c.1945A>G · rs762406949 · VCV1364588

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.051 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.051	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -5.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.71, phastCons 0.002
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	0.329	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 0.0307% African / African-American · 23/74,910 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00465% 75/1,613,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,257
European (non-Finnish)	0.00407%	24,584
Remaining individualsnot grpmax-eligible	0.0032%	31,242
East Asian	0.00223%	44,864
Admixed American	0.00167%	59,980

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.Met649Val
Coding: c.1945A>G
MANE Select: NM_144670
dbSNP: rs762406949
Type: single nucleotide variant
Location: chr12:8848831 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 649: 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.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
A2ML1 p.Gly886Val 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-met649val (accessed [today's date]).

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