Is AP1B1 p.Arg596His (c.1787G>A) pathogenic?

AP1B1 p.Arg596His (c.1787G>A) is classified Uncertain significance in AP1B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely benign (0.0972); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with AP1B1 p.Arg596His (c.1787G>A)?

AP1B1 p.Arg596His (c.1787G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP1B1 p.Arg596His (c.1787G>A) in the general population?

AP1B1 p.Arg596His (c.1787G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about AP1B1 p.Arg596His (c.1787G>A)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

AP1B1 p.Arg596His

c.1787G>A · rs776595684 · VCV3127425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -9.97	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 7.6	GERP 0.66, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 13 kb · p 0.0016 · regional, not allelic
Overall
CADD	27.6	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,048 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0125% 201/1,612,280 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,048
European (non-Finnish)	0.0161%	6,203
African / African-American	0.00933%	10,716
Remaining individualsnot grpmax-eligible	0.0032%	31,213
East Asian	0.00223%	44,820

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: AP1B1
Protein: p.Arg596His
Coding: c.1787G>A
MANE Select: NM_001127
dbSNP: rs776595684
Type: single nucleotide variant
Location: chr22:29341510 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 20 PDB
Residue 596: the 'disordered' region

Full AP1B1 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

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AP1B1 p.Ala254Thr Uncertain significance ★ ⚠ same condition
AP1B1 p.Ala352Thr Uncertain significance ★ ⚠ same condition
AP1B1 p.Ala410Thr Uncertain significance ★ ⚠ same condition
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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/ap1b1-p-arg596his (accessed [today's date]).

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