ARAP1

Chr 11

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 1

Also known as: CENTD2, cnt-d2

NCBI Gene: 116985 ENSG00000186635 UniProt: Q96P48

The ARAP1 protein is a GTPase-activating protein that regulates actin cytoskeleton remodeling and cellular trafficking processes including phagocytosis and endocytosis by modulating ARF and RHO family GTPases. Mutations cause autosomal recessive retinal dystrophy with early childhood onset, affecting photoreceptor survival due to impaired phagocytosis in retinal pigment epithelium cells. The gene shows significant constraint against loss-of-function variants (LOEUF 0.35), indicating that complete protein loss is poorly tolerated.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene contains SAM, ARF-GAP, RHO-GAP, ankyrin repeat, RAS-associating, and pleckstrin homology (PH) domains. In vitro, this protein displays RHO-GAP and phosphatidylinositol (3,4,5) trisphosphate (PIP3)-dependent ARF-GAP activity. The encoded protein associates with the Golgi, and the ARF-GAP activity mediates changes in the Golgi and the formation of filopodia. It is thought to regulate the cell-specific trafficking of a receptor protein involved in apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

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

0.35

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.35LOEUF

pLI 0.123

Z-score 6.14

OE 0.24 (0.16–0.35)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.14Z-score

OE missense 0.80 (0.75–0.85)

729 obs / 910.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.24 (0.16–0.35)

0≤0.351.4

Missense OE?0.80 (0.75–0.85)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 18 / 75.7Missense obs/exp: 729 / 910.4Syn Z: 0.98

Background carrier burden — how many people carry a rare variant somewhere in ARAP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 25

1,906 rare PASS variants

Rare truncating (LoF)

1 in 330

226 rare PASS variants

Rare synonymous (reference)

1 in 49

903 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARAP1. 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 32	1 in 700
South Asian	~43k	1 in 22	1 in 580
Remaining (unassigned)	~30k	1 in 23	1 in 170
European (Finnish)	~27k	1 in 70	1 in 490
Admixed American	~22k	1 in 28	1 in 450
African / African American	~21k	1 in 21	1 in 710
East Asian	~20k	1 in 27	1 in 380
Ashkenazi Jewish	~13k	1 in 150	1 in 2,500
Middle Eastern	~2,884	1 in 22	≈ 1 in 930

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): 32 of 33 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 33.? see exons ↓