ARHGAP6

Chr X

Rho GTPase activating protein 6

Also known as: RHOGAP6, RHOGAPX-1

NCBI Gene: 395 ENSG00000047648 UniProt: O43182

The protein functions as a GTPase-activating protein that inactivates Rho-type GTPases and regulates actin cytoskeleton dynamics during cell motility and morphological changes. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants, indicating that functional copies are essential for normal development.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of actin polymerization at the plasma membrane during several cellular processes. This protein is thought to have two independent functions, one as a GTPase-activating protein with specificity for RhoA, and another as a cytoskeletal protein that promotes actin remodeling. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.23

Clinical Summary— ARHGAP6

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 116 VUS of 315 total submissions

Explore recent and relevant literature in Research Assistant →

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?

0.23LOEUF

pLI 0.998

Z-score 4.52

OE 0.07 (0.03–0.23)

Highly constrained

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

Missense Constraint?

1.82Z-score

OE missense 0.74 (0.67–0.81)

282 obs / 382.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.23)

0≤0.351.4

Missense OE?0.74 (0.67–0.81)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 2 / 27.7Missense obs/exp: 282 / 382.3Syn Z: 0.64

This gene — mechanism propensity

0.3693th %ile

GOF

0.4579th %ile

LOF

0.77top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 39% of P/LP variants are LoF · LOEUF 0.23

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

315 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic8

VUS116

Likely Benign24

Benign20

Conflicting2

Pathogenic

Likely Pathogenic

116

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	7	2	1	15
Likely Pathogenic	4	2	2	0	8
VUS	0	115	1	0	116
Likely Benign	0	7	5	12	24
Benign	0	3	6	11	20
Conflicting	—				2
Total	9	134	16	24	185

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

View in ClinVar →

87 pathogenic / likely-pathogenic (of 107) ClinVar copy-number / structural variants overlap ARHGAP6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →