Is AGAP4 p.Pro525Ala (c.1573C>G) pathogenic?

AGAP4 p.Pro525Ala (c.1573C>G) is classified Uncertain significance in AGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.1948); Ultra-rare (popmax 0.0877%, mid).

How common is AGAP4 p.Pro525Ala (c.1573C>G) in the general population?

AGAP4 p.Pro525Ala (c.1573C>G) is ultra-rare (popmax 0.0877%, mid) (gnomAD).

What do computational predictors say about AGAP4 p.Pro525Ala (c.1573C>G)?

AlphaMissense predicts likely benign (score 0.1948) — an in-silico prediction, not a clinical call.

AGAP4 p.Pro525Ala

c.1573C>G · VCV4022832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1948 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0877%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1948	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -13.49	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	phastCons 1
Regional constraint	o/e 0.02	constrained · MANE · 451 bp · p 1.8e-45 · regional, not allelic
Overall
CADD	19.46	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 P502A vs ClinVar P525A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0877% Middle Eastern · 5/5,704 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0224%

Overall 0.00342% 55/1,606,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0877%	1,141
Remaining individualsnot grpmax-eligible	0.00482%	20,745
European (non-Finnish)	0.00374%	26,723
Admixed American	0.00337%	29,715
South Asian	0.00111%	90,462

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: AGAP4
Protein: p.Pro525Ala
Coding: c.1573C>G
MANE Select: NM_001276343
Type: single nucleotide variant
Location: chr10:45826403 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 63.70
Residue 525: the arf-gap domain; the 'disordered' region

Full AGAP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGAP4 p.Ala41Thr Uncertain significance ★ ⚠ same type
AGAP4 p.Ala464Val Uncertain significance ★ ⚠ same type
AGAP4 p.Ala466Ser Uncertain significance ★ ⚠ same type
AGAP4 p.Ala627Val Uncertain significance ★ ⚠ same type
AGAP4 p.Ala640Val Uncertain significance ★ ⚠ same type
AGAP4 p.Ala655Val Uncertain significance ★ ⚠ same type
AGAP4 p.Arg137Leu Uncertain significance ★ ⚠ same type
AGAP4 p.Arg246Gln 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/agap4-p-pro525ala (accessed [today's date]).

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