ARHGAP6

Chr X

Rho GTPase activating protein 6

Also known as: RHOGAP6, RHOGAPX-1

NCBI Gene: 395 ENSG00000047648 UniProt: O43182 OMIM: 300118

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

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

Background carrier burden — how many people carry a rare variant somewhere in ARHGAP6?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 90

831 rare PASS variants

Rare truncating (LoF)

1 in 2,600

56 rare PASS variants

Rare synonymous (reference)

1 in 100

435 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARHGAP6. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 130	1 in 2,800
South Asian	~36k	1 in 74	1 in 2,900
Remaining (unassigned)	~31k	1 in 77	1 in 2,900
European (Finnish)	~27k	1 in 270	≈ 1 in 6,400
Admixed American	~23k	1 in 81	1 in 630
African / African American	~21k	1 in 85	1 in 710
East Asian	~20k	1 in 110	≈ 1 in 6,700
Ashkenazi Jewish	~13k	1 in 700	1 in 1,900
Middle Eastern	~2,758	1 in 85	1 in 540

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 13 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: 12 of 13 (exon 2 below).? see exons ↓