Is A2ML1 p.Val822Ile (c.2464G>A) pathogenic?

A2ML1 p.Val822Ile (c.2464G>A) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-03-23). AlphaMissense: likely benign (0.0797); Ultra-rare (popmax 0.0825%, mid); Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Val822Ile (c.2464G>A)?

A2ML1 p.Val822Ile (c.2464G>A) is associated with otitis media, susceptibility to (ClinVar).

How common is A2ML1 p.Val822Ile (c.2464G>A) in the general population?

A2ML1 p.Val822Ile (c.2464G>A) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about A2ML1 p.Val822Ile (c.2464G>A)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

A2ML1 p.Val822Ile

c.2464G>A · rs201752325 · VCV426753

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	15.03	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0825% Middle Eastern · 5/6,060 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.0208% 336/1,613,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
European (non-Finnish)	0.0266%	3,758
Remaining individualsnot grpmax-eligible	0.0112%	8,930
Finnishnot grpmax-eligible	0.00939%	10,649
South Asian	0.0022%	45,530
Admixed American	0.00167%	60,016
African / African-American	0.00133%	75,012

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.Val822Ile
Coding: c.2464G>A
MANE Select: NM_144670
dbSNP: rs201752325
Type: single nucleotide variant
Location: chr12:8852210 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 822: a β-strand; 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-val822ile (accessed [today's date]).

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