Is APBB2 p.Val322Ile (c.964G>A) pathogenic?

APBB2 p.Val322Ile (c.964G>A) is classified Uncertain significance in APBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0695); Ultra-rare (popmax 0.0337%, mid).

How common is APBB2 p.Val322Ile (c.964G>A) in the general population?

APBB2 p.Val322Ile (c.964G>A) is ultra-rare (popmax 0.0337%, mid) (gnomAD).

What do computational predictors say about APBB2 p.Val322Ile (c.964G>A)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

APBB2 p.Val322Ile

c.964G>A · rs573666516 · VCV2604640

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0337%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.90	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 0.41	GERP -1.2, phastCons 0.028
Regional constraint	o/e 0.79	unconstrained · MANE · 217 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	14.11	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V321I vs ClinVar V322I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0337% Middle Eastern · 2/5,930 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.00347% 56/1,613,874 alleles · ultra-rare exomes 50/1,461,708 · genomes 6/152,166 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0337%	2,965
East Asian	0.0334%	2,992
African / African-American	0.008%	12,494
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Finnishnot grpmax-eligible	0.00312%	32,001
European (non-Finnish)	0.0022%	45,385
South Asian	0.0022%	45,528

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: APBB2
Protein: p.Val322Ile
Coding: c.964G>A
MANE Select: NM_004307
dbSNP: rs573666516
Type: single nucleotide variant
Location: chr4:40944945 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 61.73
Residue 321 UniProt numbering: the ww domain

Full APBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB2 c.20-6C>T Benign ★★ same type
APBB2 p.Ala111Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala126Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala197Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala224Asp Uncertain significance ★ ⚠ same type
APBB2 p.Ala279Val Uncertain significance ★ same type
APBB2 p.Ala436Pro Uncertain significance ★ ⚠ same type
APBB2 p.Ala436Thr 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/apbb2-p-val322ile (accessed [today's date]).

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