Is A2ML1 p.Val296Ala (c.887T>C) pathogenic?

A2ML1 p.Val296Ala (c.887T>C) is classified Benign/Likely benign in A2ML1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.2836); Ultra-rare (popmax 0.0304%, nfe).

How common is A2ML1 p.Val296Ala (c.887T>C) in the general population?

A2ML1 p.Val296Ala (c.887T>C) is ultra-rare (popmax 0.0304%, nfe) (gnomAD).

What do computational predictors say about A2ML1 p.Val296Ala (c.887T>C)?

AlphaMissense predicts likely benign (score 0.2836) — an in-silico prediction, not a clinical call.

A2ML1 p.Val296Ala

c.887T>C · rs192888493 · VCV217314

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0304%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2836	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -10.66	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 3.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	21.3	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 0.0304% European (non-Finnish) · 359/1,179,840 alleles

Filtering AF 0.0278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0267%

Overall 0.0289% 466/1,613,846 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.12%	832
Remaining individualsnot grpmax-eligible	0.0352%	2,840
European (non-Finnish)grpmax	0.0304%	3,286
Admixed American	0.0133%	7,500

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val296Ala
Coding: c.887T>C
MANE Select: NM_144670
dbSNP: rs192888493
Type: single nucleotide variant
Location: chr12:8838367 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 296: a UniProt-annotated variant site (risk factor for otitis media); a UniProt-annotated variant site (in); a β-strand

Full A2ML1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

A2ML1 p.Val296= Likely benign ★ 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
A2ML1 p.Ala1002Val 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-val296ala (accessed [today's date]).

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