Is AGAP4 p.Arg474Cys (c.1420C>T) pathogenic?

AGAP4 p.Arg474Cys (c.1420C>T) is classified Uncertain significance in AGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-12). AlphaMissense: likely benign (0.1086); Ultra-rare (popmax 0.019%, amr).

How common is AGAP4 p.Arg474Cys (c.1420C>T) in the general population?

AGAP4 p.Arg474Cys (c.1420C>T) is ultra-rare (popmax 0.019%, amr) (gnomAD).

What do computational predictors say about AGAP4 p.Arg474Cys (c.1420C>T)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

AGAP4 p.Arg474Cys

c.1420C>T · VCV3275230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -10.42	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 -2.9
Regional constraint	o/e 0.15	constrained · MANE · 470 bp · p 4.2e-35 · regional, not allelic
Overall
CADD	11.32	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 R451C vs ClinVar R474C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% Admixed American · 11/57,910 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00821%

Overall 0.00152% 24/1,576,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.019%	5,265
Remaining individualsnot grpmax-eligible	0.00162%	61,542
African / African-American	0.00145%	68,932
European (non-Finnish)	0.000948%	105,523

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.Arg474Cys
Coding: c.1420C>T
MANE Select: NM_001276343
Type: single nucleotide variant
Location: chr10:45826556 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 63.70
Residue 474: the arf-gap domain

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

Similar variants

AGAP4 p.Arg474His Uncertain significance ★ same residue
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

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-arg474cys (accessed [today's date]).

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