Is AP3B2 p.Val981Ile (c.2941G>A) pathogenic?

AP3B2 p.Val981Ile (c.2941G>A) is classified Uncertain significance in AP3B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-31). AlphaMissense: likely benign (0.1132); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with AP3B2 p.Val981Ile (c.2941G>A)?

AP3B2 p.Val981Ile (c.2941G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP3B2 p.Val981Ile (c.2941G>A) in the general population?

AP3B2 p.Val981Ile (c.2941G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about AP3B2 p.Val981Ile (c.2941G>A)?

AlphaMissense predicts likely benign (score 0.1132) — an in-silico prediction, not a clinical call.

AP3B2 p.Val981Ile

c.2941G>A · rs764083003 · VCV2084903

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1132 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1132	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 0.66, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,925 bp · p 0.51 · regional, not allelic
Overall
CADD	25.2	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 V962I vs ClinVar V981I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00223% 36/1,613,660 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00401%	24,953
Admixed American	0.00334%	29,982
Remaining individualsnot grpmax-eligible	0.0032%	31,231
European (non-Finnish)	0.00229%	43,699
South Asian	0.0011%	91,032

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: AP3B2
Protein: p.Val981Ile
Coding: c.2941G>A
MANE Select: NM_001278512
dbSNP: rs764083003
Type: single nucleotide variant
Location: chr15:82661900 (GRCh38)
Gene constraint: LOEUF 0.52 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 75.73

Full AP3B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP3B2 c.2834-3C>A Uncertain significance ★★ same condition
AP3B2 p.Ala1076Pro Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala1098Asp Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala4Val Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala633Val Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala710Thr Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala71Thr Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala819Val 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/ap3b2-p-val981ile (accessed [today's date]).

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