ARHGEF12

Chr 11

Rho guanine nucleotide exchange factor 12

Also known as: LARG, PRO2792

NCBI Gene: 23365 ENSG00000196914 UniProt: Q9NZN5 OMIM: 604763

The ARHGEF12 protein acts as a guanine nucleotide exchange factor for RhoA GTPase and regulates cellular responses to mechanical stimuli, including endothelial cell reorientation and actin stress fiber formation. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.179), suggesting mutations would cause severe developmental disorders, though specific associated diseases have not yet been established in the literature. The inheritance pattern for ARHGEF12-related conditions remains to be determined.

OMIM ResearchSummary from RefSeq, UniProt

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli working through G protein-coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. This protein has been observed to form a myeloid/lymphoid fusion partner in acute myeloid leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

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

0.18

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 8.08

OE 0.11 (0.06–0.18)

Highly constrained

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

Missense Constraint?

3.25Z-score

OE missense 0.68 (0.64–0.73)

572 obs / 836.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.18)

0≤0.351.4

Missense OE?0.68 (0.64–0.73)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 10 / 94.9Missense obs/exp: 572 / 836.3Syn Z: 1.50

Background carrier burden — how many people carry a rare variant somewhere in ARHGEF12?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 49

1,517 rare PASS variants

Rare truncating (LoF)

1 in 2,400

110 rare PASS variants

Rare synonymous (reference)

1 in 87

634 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARHGEF12. 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 69	1 in 1,900
South Asian	~43k	1 in 54	1 in 3,000
Remaining (unassigned)	~30k	1 in 42	≈ 1 in 10,000
European (Finnish)	~27k	1 in 160	≈ 1 in 27,000
Admixed American	~22k	1 in 42	1 in 1,500
African / African American	~21k	1 in 47	1 in 3,000
East Asian	~20k	1 in 56	1 in 2,800
Ashkenazi Jewish	~13k	1 in 200	1 in 1,400
Middle Eastern	~2,884	1 in 43	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): 31 of 41 coding exons well covered in gnomAD exomes; exons 2, 3, 5, 13, 15 and 5 more marginal. Genomes: all 41.? see exons ↓