ARHGAP21

Chr 10

Rho GTPase activating protein 21

Also known as: ARHGAP10

NCBI Gene: 57584 ENSG00000107863 UniProt: Q5T5U3 OMIM: 609870

ARHGAP21 functions as a GTPase-activating protein (GAP) for CDC42 and RHOA, regulating actin dynamics at the Golgi apparatus and adherens junctions. Mutations cause autosomal recessive intellectual disability with macrocephaly, seizures, and spasticity. This gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

ARHGAP21 functions preferentially as a GTPase-activating protein (GAP) for CDC42 (MIM 116952) and regulates the ARP2/3 complex (MIM 604221) and F-actin dynamics at the Golgi through control of CDC42 activity (Dubois et al., 2005 [PubMed 15793564]).[supplied by OMIM, Mar 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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.20

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 7.45

OE 0.12 (0.07–0.20)

Highly constrained

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

Missense Constraint?

0.96Z-score

OE missense 0.92 (0.87–0.97)

969 obs / 1056.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.07–0.20)

0≤0.351.4

Missense OE?0.92 (0.87–0.97)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 10 / 83.5Missense obs/exp: 969 / 1056.4Syn Z: -2.03

Background carrier burden — how many people carry a rare variant somewhere in ARHGAP21?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 28

2,087 rare PASS variants

Rare truncating (LoF)

1 in 1,800

120 rare PASS variants

Rare synonymous (reference)

1 in 55

851 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARHGAP21. 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 40	1 in 1,600
South Asian	~43k	1 in 22	1 in 1,100
Remaining (unassigned)	~30k	1 in 26	1 in 280
European (Finnish)	~27k	1 in 96	1 in 4,400
Admixed American	~22k	1 in 25	1 in 750
African / African American	~21k	1 in 25	1 in 470
East Asian	~20k	1 in 29	1 in 850
Ashkenazi Jewish	~13k	1 in 76	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 29	≈ 1 in 2,900

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): 22 of 25 coding exons well covered in gnomAD exomes; exon 4 poorly covered; exons 7, 12 marginal. Genomes: all 25.? see exons ↓