Is AGAP4 p.Arg665Trp (c.1993C>T) pathogenic?

AGAP4 p.Arg665Trp (c.1993C>T) is classified Uncertain significance in AGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0997); Very rare (popmax 0.00949%, afr).

How common is AGAP4 p.Arg665Trp (c.1993C>T) in the general population?

AGAP4 p.Arg665Trp (c.1993C>T) is very rare (popmax 0.00949%, afr) (gnomAD).

What do computational predictors say about AGAP4 p.Arg665Trp (c.1993C>T)?

AlphaMissense predicts likely benign (score 0.0997) — an in-silico prediction, not a clinical call.

AGAP4 p.Arg665Trp

c.1993C>T · VCV4022808

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00949%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0997	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -9.94	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 0.45
Regional constraint	o/e 0.02	constrained · MANE · 451 bp · p 1.8e-45 · regional, not allelic
Overall
CADD	20.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R642W vs ClinVar R665W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00949% African / African-American · 6/63,226 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00273%

Overall 0.00241% 33/1,370,328 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00949%	10,538
Admixed American	0.00913%	10,956
Remaining individualsnot grpmax-eligible	0.00368%	27,147
European (non-Finnish)	0.002%	50,113

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.Arg665Trp
Coding: c.1993C>T
MANE Select: NM_001276343
Type: single nucleotide variant
Location: chr10:45825983 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 63.70

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-arg665trp (accessed [today's date]).

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