ARHGAP4

Chr X

Rho GTPase activating protein 4

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

NCBI Gene: 393 ENSG00000089820 UniProt: P98171 OMIM: 300023

The protein functions as a GTPase-activating protein that regulates Rho family GTPases, particularly inhibiting stress fiber organization and may down-regulate Rho-like GTPases in hematopoietic cells. Genomic deletions involving this gene have been identified in patients with nephrogenic diabetes insipidus, though the specific contribution of ARHGAP4 to this phenotype requires further clarification. This gene is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.31), suggesting intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOEUF 0.31

Clinical Summary— ARHGAP4

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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.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 127 VUS of 257 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

0.69Z-score

OE missense 0.91 (0.83–0.99)

394 obs / 434.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.31)

0≤0.351.4

Missense OE?0.91 (0.83–0.99)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 5 / 33.6Missense obs/exp: 394 / 434.3Syn Z: -2.33

ClinVar Variant Classifications

257 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS127

Likely Benign26

Benign9

Conflicting1

Pathogenic

127

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	0	127	0	0	127
Likely Benign	1	13	3	9	26
Benign	0	0	6	3	9
Conflicting	—				1
Total	1	140	10	12	164

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

View in ClinVar →

170 pathogenic / likely-pathogenic (of 186) ClinVar copy-number / structural variants overlap ARHGAP4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →