Is AGAP4 p.Ala640Val (c.1919C>T) pathogenic?

AGAP4 p.Ala640Val (c.1919C>T) is classified Uncertain significance in AGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely benign (0.1108); Ultra-rare (popmax 0.0363%, eas).

How common is AGAP4 p.Ala640Val (c.1919C>T) in the general population?

AGAP4 p.Ala640Val (c.1919C>T) is ultra-rare (popmax 0.0363%, eas) (gnomAD).

What do computational predictors say about AGAP4 p.Ala640Val (c.1919C>T)?

AlphaMissense predicts likely benign (score 0.1108) — an in-silico prediction, not a clinical call.

AGAP4 p.Ala640Val

c.1919C>T · VCV3841178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1108 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1108	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.29	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 0.023	phastCons 0.002
Regional constraint	o/e 0.02	constrained · MANE · 451 bp · p 1.8e-45 · regional, not allelic
Overall
CADD	8.085	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 A617V vs ClinVar A640V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0363% East Asian · 15/41,278 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0181%

Overall 0.00308% 42/1,364,616 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0363%	2,752
Admixed American	0.0255%	3,916
South Asian	0.00837%	11,944
Remaining individualsnot grpmax-eligible	0.00737%	13,560
Finnishnot grpmax-eligible	0.00179%	55,916
European (non-Finnish)	0.000202%	495,683

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.Ala640Val
Coding: c.1919C>T
MANE Select: NM_001276343
Type: single nucleotide variant
Location: chr10:45826057 (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.Ala655Val Uncertain significance ★ ⚠ same type
AGAP4 p.Arg137Leu Uncertain significance ★ ⚠ same type
AGAP4 p.Arg246Gln Uncertain significance ★ ⚠ same type
AGAP4 p.Arg249Cys 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-ala640val (accessed [today's date]).

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