Is A2ML1 p.Val1091Ala (c.3272T>C) pathogenic?

A2ML1 p.Val1091Ala (c.3272T>C) is classified Benign in A2ML1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.2085); Low-frequency (popmax 4.26%, afr).

How common is A2ML1 p.Val1091Ala (c.3272T>C) in the general population?

A2ML1 p.Val1091Ala (c.3272T>C) is low-frequency (popmax 4.26%, afr) (gnomAD).

What do computational predictors say about A2ML1 p.Val1091Ala (c.3272T>C)?

AlphaMissense predicts likely benign (score 0.2085) — an in-silico prediction, not a clinical call.

A2ML1 p.Val1091Ala

c.3272T>C · rs61736726 · VCV241902

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2085 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.26%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2085	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -10.58	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 5.7	GERP 1.9, phastCons 0.98
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	22.9	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 4.26% African / African-American · 3,194/74,976 alleles

Filtering AF 4.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.09%

Overall 0.225% 3,638/1,614,078 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.26%	23
Remaining individualsnot grpmax-eligible	0.285%	351
Admixed American	0.278%	359
Middle Eastern	0.148%	674
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,692
South Asian	0.0121%	8,280
European (non-Finnish)	0.00576%	17,353

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.Val1091Ala
Coding: c.3272T>C
MANE Select: NM_144670
dbSNP: rs61736726
Type: single nucleotide variant
Location: chr12:8860888 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 1091: 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

Similar variants

A2ML1 p.Val1091Gly Uncertain significance ★ ⚠ same residue
A2ML1 p.Val1091Ile Uncertain significance ★ ⚠ same residue
A2ML1 c.1834-1G>T Uncertain significance ★★ same type
A2ML1 c.3264+4C>T Uncertain significance ★★ same type
A2ML1 c.3933+4A>G Uncertain significance ★★ same type
A2ML1 c.409+1G>A Uncertain significance ★★ same type
A2ML1 c.4221+2T>C Uncertain significance ★★ same type
A2ML1 c.*1+1G>A 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-val1091ala (accessed [today's date]).

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