Is AP3B2 p.Ala546Pro (c.1636G>C) pathogenic?

AP3B2 p.Ala546Pro (c.1636G>C) is classified Uncertain significance in AP3B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-18). AlphaMissense: likely pathogenic (0.9957); Ultra-rare (popmax 0.0117%, amr); Associated with developmental and epileptic encephalopathy, 48.

What condition is associated with AP3B2 p.Ala546Pro (c.1636G>C)?

AP3B2 p.Ala546Pro (c.1636G>C) is associated with developmental and epileptic encephalopathy, 48 (ClinVar).

How common is AP3B2 p.Ala546Pro (c.1636G>C) in the general population?

AP3B2 p.Ala546Pro (c.1636G>C) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about AP3B2 p.Ala546Pro (c.1636G>C)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

AP3B2 p.Ala546Pro

c.1636G>C · rs775126490 · VCV1034105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 48

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic
REVEL	0.647	pathogenic-leaning
SaProt	LLR -14.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 15 kb · p 1.1e-11 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,030 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000479% 7/1,461,682 alleles · ultra-rare

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.Ala546Pro
Coding: c.1636G>C
MANE Select: NM_001278512
dbSNP: rs775126490
Type: single nucleotide variant
Location: chr15:82676490 (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

developmental and epileptic encephalopathy, 48 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP3B2 p.Arg977Ter Pathogenic ★★ same condition
AP3B2 p.Gln839Ter Pathogenic/Likely pathogenic ★★ same condition
AP3B2 c.1110+3G>C Uncertain significance ★★ same condition
AP3B2 p.Ala1098Asp Uncertain significance ★★ ⚠ same condition
AP3B2 p.Arg977Gln Uncertain significance ★★ ⚠ same condition
AP3B2 p.Arg99Cys Uncertain significance ★★ ⚠ same condition
AP3B2 p.Asn552Tyr Uncertain significance ★★ ⚠ same condition
AP3B2 p.Asp893Glu 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-ala546pro (accessed [today's date]).

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