Is AP5B1 p.Arg696Pro (c.2087G>C) pathogenic?

AP5B1 p.Arg696Pro (c.2087G>C) is classified Uncertain significance in AP5B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely pathogenic (0.7967); Ultra-rare (popmax 0.0536%, amr).

How common is AP5B1 p.Arg696Pro (c.2087G>C) in the general population?

AP5B1 p.Arg696Pro (c.2087G>C) is ultra-rare (popmax 0.0536%, amr) (gnomAD).

What do computational predictors say about AP5B1 p.Arg696Pro (c.2087G>C)?

AlphaMissense predicts likely pathogenic (score 0.7967) — an in-silico prediction, not a clinical call.

AP5B1 p.Arg696Pro

c.2087G>C · VCV3404600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7967 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0536%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.7967	likely pathogenic · top 6% in AP5B1
SaProt	LLR -11.80	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 2,732 bp · p 8.1e-07 · regional, not allelic
Overall
CADD	26.2	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 0.0536% Admixed American · 30/55,958 alleles

Filtering AF 0.0386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0334%

Overall 0.00207% 33/1,591,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0536%	1,865
Remaining individualsnot grpmax-eligible	0.00323%	30,920
South Asian	0.00112%	89,250

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: AP5B1
Protein: p.Arg696Pro
Coding: c.2087G>C
MANE Select: NM_138368
Type: single nucleotide variant
Location: chr11:65778406 (GRCh38)
Gene constraint: LOEUF 1.424 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.29 · 2 PDB

Full AP5B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP5B1 p.Arg696His Uncertain significance ★ ⚠ same residue
AP5B1 p.Arg731Ter Pathogenic/Likely pathogenic ★★ same type
AP5B1 p.Arg857Trp Uncertain significance ★★ ⚠ same type
AP5B1 p.Leu401Phe Uncertain significance ★★ ⚠ same type
AP5B1 p.Ala345= Likely benign ★★ same type
AP5B1 p.Arg155Ter Likely pathogenic ★ same type
AP5B1 p.Leu544Pro Likely pathogenic ★ same type
AP5B1 p.Ala192Val 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/ap5b1-p-arg696pro (accessed [today's date]).

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