Is ARHGAP4 p.Ser449Arg (c.1347T>G) pathogenic?

ARHGAP4 p.Ser449Arg (c.1347T>G) is classified Uncertain significance in ARHGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: ambiguous (0.4603); Absent from gnomAD v4.1.

How common is ARHGAP4 p.Ser449Arg (c.1347T>G) in the general population?

ARHGAP4 p.Ser449Arg (c.1347T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARHGAP4 p.Ser449Arg (c.1347T>G)?

AlphaMissense predicts ambiguous (score 0.4603) — an in-silico prediction, not a clinical call.

ARHGAP4 p.Ser449Arg

c.1347T>G · VCV3781364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4603 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4603	ambiguous
REVEL	0.244	benign-leaning
SaProt	LLR -8.00	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -3.1, phastCons 0.002
Regional constraint	o/e 0.80	unconstrained · MANE · 15 kb · p 5.9e-06 · regional, not allelic
Overall
CADD	18.32	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARHGAP4
Protein: p.Ser449Arg
Coding: c.1347T>G
MANE Select: NM_001666
Type: single nucleotide variant
Location: chrX:153913282 (GRCh38)
Structure: AlphaFold pLDDT 76.48 · 1 PDB

Full ARHGAP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP4 p.Val705Ile Uncertain significance ★★ ⚠ same type
ARHGAP4 c.2415-4G>A Benign ★★ same type
ARHGAP4 c.2608-6C>T Benign ★★ same type
ARHGAP4 p.Asp420= Benign ★★ same type
ARHGAP4 p.His572= Benign ★★ same type
ARHGAP4 p.Pro627= Benign ★★ same type
ARHGAP4 c.682-292A>C Uncertain significance ★ same type
ARHGAP4 c.682-302C>G 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/arhgap4-p-ser449arg (accessed [today's date]).

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