Is AGAP4 p.Ile442Phe (c.1324A>T) pathogenic?

AGAP4 p.Ile442Phe (c.1324A>T) is classified Uncertain significance in AGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-25). AlphaMissense: ambiguous (0.3666); Very rare (popmax 9.82e-05%, nfe).

How common is AGAP4 p.Ile442Phe (c.1324A>T) in the general population?

AGAP4 p.Ile442Phe (c.1324A>T) is very rare (popmax 9.82e-05%, nfe) (gnomAD).

What do computational predictors say about AGAP4 p.Ile442Phe (c.1324A>T)?

AlphaMissense predicts ambiguous (score 0.3666) — an in-silico prediction, not a clinical call.

AGAP4 p.Ile442Phe

c.1324A>T · VCV4839688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.82e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3666	ambiguous
REVEL	0.217	benign-leaning
SaProt	LLR -13.98	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	phastCons 1
Regional constraint	o/e 0.15	constrained · MANE · 470 bp · p 4.2e-35 · regional, not allelic
Overall
CADD	19.51	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 I419F vs ClinVar I442F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.82e-05% European (non-Finnish) · 1/1,018,550 alleles

Overall 7.92e-05% 1/1,262,352 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: AGAP4
Protein: p.Ile442Phe
Coding: c.1324A>T
MANE Select: NM_001276343
Type: single nucleotide variant
Location: chr10:45826652 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 63.70
Residue 442: the arf-gap domain

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

Similar variants

AGAP4 p.Ile442Leu 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-ile442phe (accessed [today's date]).

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