ARHGAP4

Chr X

Rho GTPase activating protein 4

Also known as: C1, RGC1, RhoGAP4, SrGAP4, p115

NCBI Gene: 393ENSG00000089820UniProt: P98171

This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of small GTP-binding proteins belonging to the RAS superfamily. The protein encoded by the orthologous gene in rat is localized to the Golgi complex and can redistribute to microtubules. The rat protein stimulates the activity of some Rho GTPases in vitro. Genomic deletions of this gene and a neighboring gene have been found in patients with nephrogenic diabetes insipidus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

341
ClinVar variants
164
Pathogenic / LP
0.98
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ARHGAP4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
164 Pathogenic / Likely Pathogenic· 140 VUS of 341 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.31LOEUF
pLI 0.977
Z-score 4.57
OE 0.15 (0.08–0.31)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.69Z-score
OE missense 0.91 (0.83–0.99)
394 obs / 434.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.15 (0.08–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.83–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.22
0≤1.21.6
LoF obs/exp: 5 / 33.6Missense obs/exp: 394 / 434.3Syn Z: -2.33

ClinVar Variant Classifications

341 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic160
Likely Pathogenic4
VUS140
Likely Benign25
Benign10
Conflicting2
160
Pathogenic
4
Likely Pathogenic
140
VUS
25
Likely Benign
10
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
160
0
160
Likely Pathogenic
0
0
4
0
4
VUS
0
125
15
0
140
Likely Benign
1
13
2
9
25
Benign
0
0
6
4
10
Conflicting
—2
Total113818713341

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ARHGAP4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
ARHGAP4 mutated in a Chinese intellectually challenged family.
Liu F et al.·Gene
2016
A novel contiguous gene deletion of AVPR2 and ARHGAP4 genes in male dizygotic twins with nephrogenic diabetes insipidus and intellectual disability.
Huang L et al.·Am J Med Genet A
2012
Cai's prescription inhibits granulosa cell apoptosis through ARHGAP4 on poor ovarian responders.
Wang Z et al.·J Ovarian Res
2024
Immunological profile in a family with nephrogenic diabetes insipidus with a novel 11 kb deletion in AVPR2 and ARHGAP4 genes.
Fujimoto M et al.·BMC Med Genet
2008Case report
Rho GTPase-activating protein 4 is upregulated in Kidney Renal Clear Cell Carcinoma and associated with poor prognosis and immune infiltration.
Xiao X et al.·Cancer Biomark
2024
E2F expression profiling-based subtypes in head and neck squamous cell carcinoma: clinical relevance, prognostic implications, and personalized therapy.
Jiang H et al.·World J Surg Oncol
2025
Two novel types of contiguous gene deletion of the AVPR2 and ARHGAP4 genes in unrelated Japanese kindreds with nephrogenic diabetes insipidus.
Demura M et al.·Hum Mutat
2002Case report
Contiguous 22.1-kb deletion embracing AVPR2 and ARHGAP4 genes at novel breakpoints leads to nephrogenic diabetes insipidus in a Chinese pedigree.
Bai Y et al.·BMC Nephrol
2018
Characterization of macrophages in head and neck squamous cell carcinoma and development of MRG-based risk signature.
Liu L et al.·Sci Rep
2024
FNBP2 gene on human chromosome 1q32.1 encodes ARHGAP family protein with FCH, FBH, RhoGAP and SH3 domains.
Katoh M et al.·Int J Mol Med
2003
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools