ARHGAP42

Chr 11

Rho GTPase activating protein 42

Also known as: AD031, GRAF3, TMEM133

NCBI Gene: 143872 ENSG00000165895 UniProt: A6NI28 OMIM: 615936

This gene encodes a Rho GTPase-activating protein that inhibits RhoA activity in vascular smooth muscle cells to regulate vascular tone and blood pressure. The gene is highly constrained against loss-of-function variation (pLI=1.0, LOEUF=0.16), suggesting that mutations would likely cause severe developmental disorders, though specific pediatric phenotypes have not yet been established. Currently, only intronic variants affecting gene expression have been associated with blood pressure regulation in adults.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a Rho GTPase-activating protein (RhoGAP), and member of the GRAF or BAR-PH family of proteins. Expression of this gene is enriched in vascular smooth muscle cells and the encoded protein inhibits RhoA activity to regulate vascular tone and control blood pressure. A mutation in the first intron of this gene modulates its expression and is associated with reduced blood pressure in human patients with borderline hypertension. [provided by RefSeq, Jul 2017]

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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.15

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.15LOEUF

pLI 1.000

Z-score 6.16

OE 0.06 (0.03–0.15)

Highly constrained

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

Missense Constraint?

2.96Z-score

OE missense 0.58 (0.52–0.65)

228 obs / 393.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.15)

0≤0.351.4

Missense OE?0.58 (0.52–0.65)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 3 / 50.0Missense obs/exp: 228 / 393.5Syn Z: 1.94

Background carrier burden — how many people carry a rare variant somewhere in ARHGAP42?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 65

988 rare PASS variants

Rare truncating (LoF)

1 in 740

129 rare PASS variants

Rare synonymous (reference)

1 in 140

456 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARHGAP42. 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)	~556k	1 in 92	1 in 3,200
South Asian	~43k	1 in 67	1 in 800
Remaining (unassigned)	~30k	1 in 61	1 in 2,000
European (Finnish)	~27k	1 in 130	1 in 2,800
Admixed American	~22k	1 in 100	1 in 2,500
African / African American	~21k	1 in 62	1 in 820
East Asian	~20k	1 in 68	1 in 1,800
Ashkenazi Jewish	~13k	1 in 530	1 in 1,100
Middle Eastern	~2,884	1 in 78	none seen

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): 17 of 24 coding exons well covered in gnomAD exomes; exons 3, 4, 5, 6, 9 and 2 more marginal. Genomes: 23 of 24 (exon 6 below).? see exons ↓