Is A2ML1 p.Ile646Thr (c.1937T>C) pathogenic?

A2ML1 p.Ile646Thr (c.1937T>C) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0584); Rare (popmax 0.501%, afr); Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Ile646Thr (c.1937T>C)?

A2ML1 p.Ile646Thr (c.1937T>C) is associated with otitis media, susceptibility to (ClinVar).

How common is A2ML1 p.Ile646Thr (c.1937T>C) in the general population?

A2ML1 p.Ile646Thr (c.1937T>C) is rare (popmax 0.501%, afr) (gnomAD).

What do computational predictors say about A2ML1 p.Ile646Thr (c.1937T>C)?

AlphaMissense predicts likely benign (score 0.0584) — an in-silico prediction, not a clinical call.

A2ML1 p.Ile646Thr

c.1937T>C · rs150488553 · VCV697219

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0584 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.501%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.0584	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -5.52	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 -0.68	GERP 1.3
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	11.73	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 0.501% African / African-American · 376/75,052 alleles

Filtering AF 0.459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.443%

Overall 0.0287% 464/1,614,168 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.501%	200
Remaining individualsnot grpmax-eligible	0.064%	1,563
Middle Eastern	0.033%	3,031
Admixed American	0.03%	3,334
South Asian	0.00439%	22,769
European (non-Finnish)	0.00203%	49,168

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.Ile646Thr
Coding: c.1937T>C
MANE Select: NM_144670
dbSNP: rs150488553
Type: single nucleotide variant
Location: chr12:8848823 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 646: 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.Ile646Asn Uncertain significance ★ ⚠ 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
A2ML1 p.Gly777Arg 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-ile646thr (accessed [today's date]).

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