ARL2BP
protein-codingADP ribosylation factor like GTPase 2 binding protein
Gene summary
ADP-ribosylation factor (ARF)-like proteins (ARLs) comprise a functionally distinct group of the ARF family of RAS-related GTPases. The protein encoded by this gene binds to ARL2.GTP with high affinity but does not interact with ARL2.GDP, activated ARF, or RHO proteins. The lack of detectable membrane association of this protein or ARL2 upon activation of ARL2 is suggestive of actions distinct from those of the ARFs. This protein is considered to be the first ARL2-specific effector identified, due to its interaction with ARL2.GTP but lack of ARL2 GTPase-activating protein activity. [provided by RefSeq, Jul 2008]
- RP66
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~8.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014186
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014186
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: ClinGen
*ARL2BP* was first described as a Retinitis Pigmentosa (RP)-causing gene in 2013 (Davidson et al. 2013, PMID: 23849777). Since that time, the range of common patient phenotypes has expanded to include reduced visual acuity, macular atrophy, nyctalopia, photopsia, constriction of peripheral visual field, photophobia, and chorioretinal atrophy. Additional extraocular phenotypes such as situs inversus totalis, asthenozoospermia, or reduced sperm motility have been reported as well. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic *ARL2BP* loss of function) have been found to be consistent among patients diagnosed with retinitis pigmentosa 82 with or without situs inversus, while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *ARL2BP* variants have been lumped into a single disease entity, referred to as "ARL2BP-related ciliopathy". This curation includes 7 variants ( 2 frameshift, 1 missense, and 4 disrupting canonical splice sites) that have collectively been reported in 7 probands in 5 publications (PMID: 23849777, 27790702, 31425546, 36507858, 38649918). All of the included probands were born into consanguineous families, and all were diagnosed during adulthood after experiencing a variety of ocular symptoms during childhood. Overall, the mechanism of pathogenicity appears to be biallelic loss of function, as indicated by the variant types found in the probands. This gene-disease relationship is also supported by experimental evidence that ARL2BP protein localizes to the base of the cilia in mouse fibroblast cells and human retinal pigment epithelial cells (PMID: 23849777). This matches the localizations of the retinopathy-related gene products RPGR, RP1 and MAK to the ciliary basal body and rootlet (PMID: 29718757). In the absence of ARL2BP, the length and formation of cilia are affected, and photoreceptor outer segment does not develop normally or have correct doublet microtubule formation, axoneme extension, or disk alignment (PMID: 23849777). Multiple mouse knockout models, including a global knockout generated by CRISPR-Cas9, showed loss of photoreceptor nuclei in the outer nuclear layer, consistent with retinal layer atrophy in affected human patients (PMID: 29718757, PMID: 31425546). The mouse model also exhibited situs inversus and immotile sperm (PMID: 31425546). In conclusion, *ARL2BP* has a definitive association with ARL2BP-related ciliopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on January 2nd, 2025 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0014186
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Ophthalmologic
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
Comments: Although described patients did not suffer from sequelae as severe as have been reported in other types of ciliary dyskinesia, similar medical interventions may in theory be warranted
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ARL2BP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012106.4. 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 | 18 | 18 | ||||
| missense | 54 | 2 | 56 | |||
| nonsense | 3 | 1 | 4 | |||
| start loss | 0 | |||||
| frameshift | 6 | 2 | 8 | |||
| splice donor/acceptor (+/-2bp) | 5 | 2 | 4 | 11 | ||
| Total | 14 | 4 | 59 | 20 | 0 | 97 |
Highest pathogenic variant AF is 0.0000814528
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036238.1 | 6 | MANE Select | |
| Ensembl | ENSP00000219204.3 | 6 | MANE Select | |
| Ensembl | ENSP00000457465.1 | 5 | Standard | |
| Ensembl | ENSP00000457465.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Metabolism
- Regulation of insulin secretion
- Integration of energy metabolism
Biological Process
- signal transduction
- positive regulation of tyrosine phosphorylation of STAT protein
- regulation of catalytic activity
- regulation of insulin secretion
- maintenance of protein location in nucleus
Molecular Function
- transcription coactivator activity
- protein binding
- GTPase regulator activity
Cellular Component
- nucleus
- mitochondrial intermembrane space
- mitochondrial matrix
- centrosome
- spindle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000219204
- Coding exons
- 6
- Length
- 8507
- Individuals with no LoFs
- 125695
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 53
- Defined
- 125748
- p
- 0.000211
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.826 | 64 | 85.5 | 0.749 | 0.00000414 | 1075 |
| Missense (PolyPhen) | 10 | 20.007 | 0.49982 | 327 | ||
| Synonymous | 0.461 | 30 | 33.4 | 0.899 | 0.00000169 | 289 |
| Loss of Function | 0.755 | 8 | 10.7 | 0.751 | 6.29e-7 | 121 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00025 | rare |
| Latino/Admixed American | 0.00010 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.0010 | 0.0010 | notable |
| European (Non-Finnish) | 0.00016 | 0.00015 | rare |
| South Asian | 0.00014 | 0.00013 | rare |
| Other | 0.00035 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Together with ARL2, plays a role in the nuclear translocation, retention and transcriptional activity of STAT3. May play a role as an effector of ARL2. {ECO:0000269|PubMed:18234692}.;
Recessive Scores
- pRec
- 0.0682
Intolerance Scores
- LoFtool
- 0.709
- RVIS EVS
- 0.13
- RVIS percentile EVS
- 62.74
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.801