Is AP5B1 p.Ala620Pro (c.1858G>C) pathogenic?

AP5B1 p.Ala620Pro (c.1858G>C) is classified Uncertain significance in AP5B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: ambiguous (0.3709); Very rare (popmax 0.0064%, nfe).

How common is AP5B1 p.Ala620Pro (c.1858G>C) in the general population?

AP5B1 p.Ala620Pro (c.1858G>C) is very rare (popmax 0.0064%, nfe) (gnomAD).

What do computational predictors say about AP5B1 p.Ala620Pro (c.1858G>C)?

AlphaMissense predicts ambiguous (score 0.3709) — an in-silico prediction, not a clinical call.

AP5B1 p.Ala620Pro

c.1858G>C · rs375089955 · VCV2611132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0064%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3709	ambiguous
SaProt	LLR -11.23	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -2.3, phastCons 0.37
Regional constraint	o/e 1.15	unconstrained · MANE · 2,732 bp · p 8.1e-07 · regional, not allelic
Overall
CADD	17.73	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0064% European (non-Finnish) · 75/1,172,642 alleles

Filtering AF 0.00523% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00477%

Overall 0.0047% 75/1,594,886 alleles · very 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: AP5B1
Protein: p.Ala620Pro
Coding: c.1858G>C
MANE Select: NM_138368
dbSNP: rs375089955
Type: single nucleotide variant
Location: chr11:65778635 (GRCh38)
Gene constraint: LOEUF 1.424 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.29 · 2 PDB
Residue 620: an α-helix

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

Similar variants

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
AP5B1 p.Ala239Val 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-ala620pro (accessed [today's date]).

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