Is AP3B2 p.Arg686Trp (c.2056C>T) pathogenic?

AP3B2 p.Arg686Trp (c.2056C>T) is classified Uncertain significance in AP3B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: ambiguous (0.4463); Ultra-rare (popmax 0.0495%, mid).

How common is AP3B2 p.Arg686Trp (c.2056C>T) in the general population?

AP3B2 p.Arg686Trp (c.2056C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about AP3B2 p.Arg686Trp (c.2056C>T)?

AlphaMissense predicts ambiguous (score 0.4463) — an in-silico prediction, not a clinical call.

AP3B2 p.Arg686Trp

c.2056C>T · rs1033207460 · VCV1445747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4463 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4463	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -9.27	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,925 bp · p 0.51 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R667W vs ClinVar R686W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,056 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.00227% 33/1,456,374 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
East Asian	0.00223%	44,792
European (non-Finnish)	0.00221%	45,292
Admixed American	0.00169%	59,298
African / African-American	0.00133%	74,980
South Asian	0.00112%	89,504

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.Arg686Trp
Coding: c.2056C>T
MANE Select: NM_001278512
dbSNP: rs1033207460
Type: single nucleotide variant
Location: chr15:82664916 (GRCh38)
Gene constraint: LOEUF 0.52 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 75.73
Residue 686: the 'disordered' region

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

Similar variants

AP3B2 p.Arg686= Likely benign ★★ same residue
AP3B2 c.114-1G>A Likely pathogenic ★★ same type
AP3B2 p.Arg977Ter Pathogenic ★★ same type
AP3B2 p.Gln839Ter Pathogenic/Likely pathogenic ★★ same type
AP3B2 c.1110+3G>C Uncertain significance ★★ same type
AP3B2 c.1853-5C>A Uncertain significance ★★ same type
AP3B2 c.2834-3C>A Uncertain significance ★★ same type
AP3B2 p.Ala1076Pro 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/ap3b2-p-arg686trp (accessed [today's date]).

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