ARF1
protein-codingADP ribosylation factor 1, the group of Receptor ligands|ARF GTPase family|MicroRNA protein coding host genes
Gene summary
ADP-ribosylation factor 1 (ARF1) is a member of the human ARF gene family. The family members encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking as activators of phospholipase D. The gene products, including 6 ARF proteins and 11 ARF-like proteins, constitute a family of the RAS superfamily. The ARF proteins are categorized as class I (ARF1, ARF2 and ARF3), class II (ARF4 and ARF5) and class III (ARF6), and members of each class share a common gene organization. The ARF1 protein is localized to the Golgi apparatus and has a central role in intra-Golgi transport. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020341
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0032588
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0032588
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0032588
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0020341
Submitter: ClinGen
ARF1 was first reported in relation to autosomal dominant periventricular nodular heterotopia in 2016 (Ge et al., PMID: 28868155). Nine variants (missense, frameshift, nonsense) that have been reported in over 10 probands in 4 publications (PMIDs: 28868155, 34353862, 36345169, 37185208) are included in this curation. Not all probands have periventricular nodular heterotopia; the range of the phenotype includes variable facial anomalies, developmental delay, intellectual disability, seizures, and motor abnormalities. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be haploinsufficiency. This gene-disease relationship is also supported by experimental evidence (mouse model, functional alteration evidence, rescue evidence; PMIDs: 25305484, 37118341, 38014604). Mutant mice show embryonic lethality. Functional alteration indicates abnormal mitotic spindle assembly, demyelination, and neuronal degradation in the mutants. Abnormal mitotic spindle assembly is partially reduced in mutants that receive ARF1 mRNA supplementation. In summary, there is definitive evidence supporting the relationship between ARF1 and autosomal dominant periventricular nodular heterotopia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date 6/25/2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0032588
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ARF1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001658.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 8 | 2 | 10 | |||
| missense | 6 | 8 | 18 | 32 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 6 | 8 | 21 | 8 | 2 | 45 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001649.1 | 4 | MANE Select | |
| Ensembl | ENSP00000272102.5 | 4 | MANE Select | |
| RefSeq | NP_001019397.1 | 4 | Standard | |
| RefSeq | NP_001019398.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| arf1 | Danio rerio | Structure: post-vent region Quality: increased curvature abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Legionellosis - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
- Vibrio cholerae infection - Homo sapiens (human)
- Phospholipase D signaling pathway - Homo sapiens (human)
- Cell Cycle
Biological Process
- regulation of receptor internalization
- phosphatidylinositol biosynthetic process
- cellular copper ion homeostasis
- intracellular protein transport
- Golgi to plasma membrane transport
Molecular Function
- magnesium ion binding
- RNA binding
- GTPase activity
- protein binding
- GTP binding
Cellular Component
- Golgi membrane
- cytoplasm
- late endosome
- peroxisomal membrane
- Golgi apparatus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000541182
- Coding exons
- 4
- Length
- 16552
- Individuals with no LoFs
- 125585
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125589
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.39 | 17 | 122 | 0.139 | 0.00000807 | 1199 |
| Missense (PolyPhen) | 1 | 29.103 | 0.034361 | 378 | ||
| Synonymous | -0.370 | 53 | 49.7 | 1.07 | 0.00000352 | 348 |
| Loss of Function | 2.53 | 0 | 7.44 | 0.00 | 3.16e-7 | 84 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000034 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP- ribosyltransferase. Involved in protein trafficking among different compartments. Modulates vesicle budding and uncoating within the Golgi complex. Deactivation induces the redistribution of the entire Golgi complex to the endoplasmic reticulum, suggesting a crucial role in protein trafficking. In its GTP-bound form, its triggers the association with coat proteins with the Golgi membrane. The hydrolysis of ARF1-bound GTP, which is mediated by ARFGAPs proteins, is required for dissociation of coat proteins from Golgi membranes and vesicles. The GTP-bound form interacts with PICK1 to limit PICK1-mediated inhibition of Arp2/3 complex activity; the function is linked to AMPA receptor (AMPAR) trafficking, regulation of synaptic plasicity of excitatory synapses and spine shrinkage during long-term depression (LTD).;
Recessive Scores
- pRec
- 0.221
Intolerance Scores
- RVIS EVS
- -0.14
- RVIS percentile EVS
- 42.88
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.801
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Low | Low | Low |
| Primary Immunodeficiency | Low | Low | Low |
| Cancer | Low | Low | Low |