ARFGAP1

Chr 20

ARF GTPase activating protein 1

Also known as: ARF1GAP, HRIHFB2281

NCBI Gene: 55738 ENSG00000101199 UniProt: Q8N6T3 OMIM: 608377

ARFGAP1 encodes a GTPase-activating protein that promotes hydrolysis of ARF1-bound GTP, which is essential for dissociation of coat proteins from Golgi-derived membranes and vesicles to enable proper vesicle fusion and membrane trafficking. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities. The gene shows significant constraint against loss-of-function variants (LOEUF 0.599), consistent with its essential cellular role.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a GTPase-activating protein, which associates with the Golgi apparatus and which interacts with ADP-ribosylation factor 1. The encoded protein promotes hydrolysis of ADP-ribosylation factor 1-bound GTP and is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. The activity of this protein is stimulated by phosphoinosides and inhibited by phosphatidylcholine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.60

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.002

Z-score 3.19

OE 0.35 (0.22–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.42Z-score

OE missense 0.93 (0.83–1.03)

238 obs / 257.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.22–0.60)

0≤0.351.4

Missense OE?0.93 (0.83–1.03)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 10 / 28.3Missense obs/exp: 238 / 257.1Syn Z: -1.82

Background carrier burden — how many people carry a rare variant somewhere in ARFGAP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 49

885 rare PASS variants

Rare truncating (LoF)

1 in 870

128 rare PASS variants

Rare synonymous (reference)

1 in 110

317 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARFGAP1. 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 62	1 in 1,100
South Asian	~43k	1 in 44	1 in 460
Remaining (unassigned)	~30k	1 in 38	1 in 490
European (Finnish)	~27k	1 in 130	1 in 910
Admixed American	~22k	1 in 49	1 in 1,300
African / African American	~21k	1 in 37	1 in 620
East Asian	~20k	1 in 60	1 in 910
Ashkenazi Jewish	~13k	1 in 210	1 in 2,600
Middle Eastern	~2,884	1 in 68	1 in 540

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 12 coding exons well covered in gnomAD exomes and genomes.? see exons ↓