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…

MultiplemechanismLOEUF 0.60

Clinical Summary— ARFGAP1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

69 VUS of 99 total submissions

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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

This gene — mechanism propensity

0.7326th %ile

GOF

0.7029th %ile

LOF

0.3260th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

99 submitted variants in ClinVar

ClinVar

Classification Summary

VUS69

Likely Benign8

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	69	0	69
Likely Benign	6	2	8
Benign	0	0	0
Total	75	2	77

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

49 pathogenic / likely-pathogenic (of 75) ClinVar copy-number / structural variants overlap ARFGAP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →