Is A2ML1 p.Arg1122Trp (c.3364C>T) pathogenic?

A2ML1 p.Arg1122Trp (c.3364C>T) is classified Benign/Likely benign in A2ML1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0867); Common (popmax 80.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Arg1122Trp (c.3364C>T)?

A2ML1 p.Arg1122Trp (c.3364C>T) is associated with otitis media, susceptibility to (ClinVar).

What do computational predictors say about A2ML1 p.Arg1122Trp (c.3364C>T)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

A2ML1 p.Arg1122Trp

Q: How common is A2ML1 p.Arg1122Trp (c.3364C>T) in the general population?

A2ML1 p.Arg1122Trp (c.3364C>T) is common (popmax 80.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3364C>T · rs1860967 · VCV384669

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 80.9%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -10.24	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 0.11	GERP -0.6
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	22.1	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 80.9% East Asian · 36,281/44,874 alleles

Filtering AF 80.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 79.9%

Overall 39.1% 631,030/1,613,616 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	80.9%	1
Admixed American	58.3%	2
South Asian	49.2%	2
Finnishnot grpmax-eligible	42.6%	2
Remaining individualsnot grpmax-eligible	40.6%	2
Middle Eastern	38.3%	3
European (non-Finnish)	37.2%	3
Ashkenazi Jewishnot grpmax-eligible	32.9%	3
Amishnot grpmax-eligible	26.1%	4
African / African-American	15%	7

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.Arg1122Trp
Coding: c.3364C>T
MANE Select: NM_144670
dbSNP: rs1860967
Type: single nucleotide variant
Location: chr12:8861159 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 1122: a disulfide bond; an α-helix; a UniProt-annotated variant site (risk factor for otitis media); a UniProt-annotated variant site (in)

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.Arg1122= Likely benign ★★ same residue
A2ML1 p.Arg1122Gln Likely benign ★ same residue
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

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-arg1122trp (accessed [today's date]).

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