ARL2

Summary

ARL2 (ARF like GTPase 2, HGNC:693) is a protein-coding gene on chromosome 11q13.1, encoding ADP-ribosylation factor-like protein 2 (P36404). Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). It is a common-essential gene (DepMap: required in 99.1% of cancer cell lines).

This gene encodes a small GTP-binding protein of the RAS superfamily which functions as an ADP-ribosylation factor (ARF). The encoded protein is one of a functionally distinct group of ARF-like genes.

Source: NCBI Gene 402 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1 (Strong, GenCC)
• Clinical variants (ClinVar): 30 total — 1 pathogenic
• Phenotypes (HPO): 7
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_001667

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:693
Approved symbol	ARL2
Name	ARF like GTPase 2
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	ARFL2
Ensembl gene	ENSG00000213465
Ensembl biotype	protein_coding
OMIM	601175
Entrez	402

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 retained_intron

ENST00000246747, ENST00000524585, ENST00000529254, ENST00000529384, ENST00000531533, ENST00000533729, ENST00000885663, ENST00000923998

RefSeq mRNA: 2 — MANE Select: NM_001667 NM_001199745, NM_001667

CCDS: CCDS55770, CCDS8088

Canonical transcript exons

ENST00000246747 — 5 exons

Exon	Start	End
ENSE00000729668	65020419	65020499
ENSE00001119977	65021721	65022184
ENSE00001270497	65014160	65014272
ENSE00003528028	65018571	65018733
ENSE00003539756	65018364	65018474

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 98.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.6830 / max 127.4743, expressed in 1734 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115010	39.6077	1808
115011	14.9083	1728
115013	0.7747	333

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	98.80	gold quality
nucleus accumbens	UBERON:0001882	98.78	gold quality
apex of heart	UBERON:0002098	98.72	gold quality
caudate nucleus	UBERON:0001873	98.41	gold quality
putamen	UBERON:0001874	98.32	gold quality
tibial nerve	UBERON:0001323	98.24	gold quality
right frontal lobe	UBERON:0002810	98.18	gold quality
left coronary artery	UBERON:0001626	98.13	gold quality
ascending aorta	UBERON:0001496	98.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.12	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.12	gold quality
thoracic aorta	UBERON:0001515	98.11	gold quality
lower esophagus	UBERON:0013473	98.10	gold quality
right atrium auricular region	UBERON:0006631	98.09	gold quality
aorta	UBERON:0000947	98.01	gold quality
popliteal artery	UBERON:0002250	98.01	gold quality
left testis	UBERON:0004533	98.01	gold quality
tibial artery	UBERON:0007610	98.01	gold quality
mucosa of stomach	UBERON:0001199	98.00	gold quality
coronary artery	UBERON:0001621	97.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.95	gold quality
right testis	UBERON:0004534	97.95	gold quality
body of uterus	UBERON:0009853	97.89	gold quality
gastrocnemius	UBERON:0001388	97.88	gold quality
right coronary artery	UBERON:0001625	97.83	gold quality
descending thoracic aorta	UBERON:0002345	97.83	gold quality
spinal cord	UBERON:0002240	97.80	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.79	gold quality
prefrontal cortex	UBERON:0000451	97.63	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.62	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.16
E-CURD-112	yes	8.37
E-MTAB-7316	yes	7.21
E-MTAB-6524	no	357.45
E-MTAB-7303	no	237.65
E-MTAB-9388	no	11.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

miRNA regulators (miRDB)

26 targeting ARL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-4687-5P	99.14	66.26	488
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-503-5P	97.87	66.83	575
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-1288-3P	96.86	66.95	536
HSA-MIR-5090	93.28	60.86	94
HSA-MIR-6775-5P	92.43	61.00	132
HSA-MIR-4258	90.68	62.19	164

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 22)

• C. elegans evl-20 gene encodes a functional homolog of human ARL2. Elimination of evl-20 function results in abnormal vulval, gonad, and male tail development and disrupts embryonic proliferation, hypodermal enclosure, and elongation. (PMID:12015966)
• Arl2 is present in centrosomes and propose that its action in regulating tubulin polymerization is mediated at centrosomes (PMID:16525022)
• In summary, alterations in Arl2 protein content were found to be associated with modifications in tubulin pools, microtubule dynamics as well as cell cycle progression. (PMID:17188265)
• ARL2 and beta-tubulin cofactor D participate in AJC disassembly and epithelial depolarization (PMID:17704193)
• Arl2 and Arl3 interactions were characterized. (PMID:18588884)
• Arl2 could, via protein phosphatase 2A , influence p53 phosphorylation status. (PMID:18818514)
• Crystal structure of the ARL2-GTP-BART complex reveals a novel recognition and binding mode of small GTPase with effector. (PMID:19368893)
• Data show that bovine and human TBCD have functionally identical roles in tubulin heterodimer assembly, and that the inability of human TBCD to disrupt microtubule integrity can be overcome by siRNA-mediated suppression of expression of Arl2. (PMID:20740604)
• a novel function of miR-16 targeting ARL2 in modulating proliferation and cell cycle progression. (PMID:21199864)
• The G proteins Arl2 acts in a GTP-dependent manner as allosteric release factors for farnesylated cargo. (PMID:22002721)
• MiR-195 regulates cell apoptosis in a context-dependent manner through directly targeting ARL2. (PMID:23807224)
• We hypothesize that ARL2 plays essential roles inside mitochondria along with other cellular functions, at least in part to provide coupling of regulation between these essential cell processes. (PMID:24911211)
• Results identified ARL2 and TBCD, as important in tubulin folding and microtubule dynamics. Both ARL2 and TBCD also localize to centrosomes. A growing body of evidence also has found roles for ARL2 inside mitochondria, as a regulator of mitochondrial fusion, and in the traffic of farnesylated cargos between membranes and specifically to cilia and photoreceptor cells. [review] (PMID:27400436)
• Novel Biochemical and Structural Insights into the Interaction of Myristoylated Cargo with Unc119 Protein and Their Release by Arl2/3. (PMID:27481943)
• In conclusion, our study revealed that miR-214 acts as a tumor suppressor via inhibiting proliferation, migration and invasion of cervical cancer cells through targeting ARL2, and that both miR-214 and ARL2 may serve as prognostic or therapeutic targets for cervical cancer. (PMID:28137590)
• conclude that the TBCD*ARL2*beta-tubulin complex represents a functional intermediate in the beta-tubulin folding pathway whose activity is regulated by the cycling of nucleotides on ARL2 (PMID:28970104)
• High ARL2 expression is associated with Osteosarcoma. (PMID:29265919)
• Decreased ARL2 expression level was clinically correlated to the higher grades and poorer outcomes of glioma patients. ARL2 overexpression attenuated the proliferation, clone formation, migration, invasive and tumorigenic capabilities of glioma cells by regulating the expression of receptor tyrosine kinase AXL. (PMID:29843637)
• Results suggest that ELMOD2 is functioning as an effector downstream of ARL2 and upstream of the mitofusins to promote mitochondrial fusion. Data provide insights into the pathway by which mitochondrial fusion is regulated in the cell. (PMID:30865555)
• we uncover ARL2 as a novel candidate gene for MRCS syndrome and suggest a mitochondria-related mechanism of the first ARL2 variant through site-directed mutagenesis studies. (PMID:30945270)
• Suppressed microRNA-195-5p expression in mycosis fungoides promotes tumor cell proliferation. (PMID:32492224)
• ARL2 is required for homologous recombination repair and colon cancer stem cell survival. (PMID:35567502)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	arl2	ENSDARG00000069496
mus_musculus	Arl2	ENSMUSG00000024944
rattus_norvegicus	Arl2	ENSRNOG00000021010
drosophila_melanogaster	Arl2	FBGN0004908
caenorhabditis_elegans		WBGENE00001358

Paralogs (30): ARF5 (ENSG00000004059), SAR1A (ENSG00000079332), ARFRP1 (ENSG00000101246), TRIM23 (ENSG00000113595), ARL6 (ENSG00000113966), ARL1 (ENSG00000120805), ARL4A (ENSG00000122644), ARL8B (ENSG00000134108), ARF3 (ENSG00000134287), ARL3 (ENSG00000138175), ARL5C (ENSG00000141748), ARF1 (ENSG00000143761), ARL8A (ENSG00000143862), ARL11 (ENSG00000152213), SAR1B (ENSG00000152700), ARL5A (ENSG00000162980), ARF6 (ENSG00000165527), ARL5B (ENSG00000165997), ARF4 (ENSG00000168374), ARL13B (ENSG00000169379), ARL13A (ENSG00000174225), ARL10 (ENSG00000175414), ARL4D (ENSG00000175906), ARL14 (ENSG00000179674), ARL15 (ENSG00000185305), ARL17A (ENSG00000185829), ARL4C (ENSG00000188042), ARL9 (ENSG00000196503), ARL16 (ENSG00000214087), ARL17B (ENSG00000228696)

Protein

Protein identifiers

ADP-ribosylation factor-like protein 2 — P36404 (reviewed: P36404)

All UniProt accessions (2): P36404, Q53YD8

UniProt curated annotations — full annotation on UniProt →

Function. Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. Regulates formation of new microtubules and centrosome integrity. Prevents the TBCD-induced microtubule destruction. Participates in association with TBCD, in the disassembly of the apical junction complexes. Antagonizes the effect of TBCD on epithelial cell detachment and tight and adherens junctions disassembly. Together with ARL2, plays a role in the nuclear translocation, retention and transcriptional activity of STAT3. Component of a regulated secretory pathway involved in Ca(2+)-dependent release of acetylcholine. Required for normal progress through the cell cycle. Also regulates mitochondrial integrity and function.

Subunit / interactions. Found in a complex with ARL2, ARL2BP and SLC25A6. Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD. Found in a complex with ARL2, ARL2BP and SLC25A4. The GTP-bound form interacts with PDE6D. Interacts with ELMOD2. The GTP-bound form interacts with ARL2BP. Interacts, preferentially in its GDP-bound state, with TBCD. Interacts with UNC119.

Subcellular location. Mitochondrion intermembrane space. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Nucleus.

Post-translational modifications. Not N-myristoylated.

Disease relevance. Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1 (MRCS1) [MIM:619082] An autosomal dominant ocular disorder characterized by poor visual acuity in early childhood, due to congenital cataract and microcornea followed by rod-cone dystrophy, with later development of posterior staphyloma. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the small GTPase superfamily. Arf family.

Isoforms (2)

UniProt ID	Names	Canonical?
P36404-1	1	yes
P36404-2	2

RefSeq proteins (2): NP_001186674, NP_001658* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005225	Small_GTP-bd	Domain
IPR006689	Small_GTPase_ARF/SAR	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR044612	ARL2/3	Family
IPR045873	Arl2	Family

Pfam: PF00025

Enzyme classification (BRENDA):

• EC 3.6.5.2 — small monomeric GTPase (BRENDA: 49 organisms, 138 substrates, 55 inhibitors, 5 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	—	0

UniProt features (41 total): mutagenesis site 13, helix 9, strand 6, binding site 4, sequence variant 2, initiator methionine 1, chain 1, turn 1, modified residue 1, lipid moiety-binding region 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9M1J	ELECTRON MICROSCOPY	2.14
9M1M	ELECTRON MICROSCOPY	2.21
9M1N	ELECTRON MICROSCOPY	2.24
3DOE	X-RAY DIFFRACTION	2.25
9M1K	ELECTRON MICROSCOPY	2.45
9M1I	ELECTRON MICROSCOPY	2.48
9M1L	ELECTRON MICROSCOPY	2.55
3DOF	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36404-F1	94.31	0.87

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 23–30; 66–70; 68; 125–128

Post-translational modifications (3): 45, 2, 71

Mutagenesis-validated functional residues (13):

Position	Phenotype
3	reduces interaction with arl2bp.
4	does not reduce interaction with arl2bp.
4	reduces interaction with arl2bp.
6	reduces interaction with arl2bp.
7	does not reduce interaction with arl2bp.
7	reduces interaction with arl2bp.
30	does not inhibit the interaction with tbcd and rescues the tbcd-induced microtubule destruction. reduces interaction wit
47	does not inhibit the interaction with tbcd and rescues the tbcd-induced microtubule destruction.
50	reduces interaction with arl2bp. inhibits the interaction with tbcd and rescues the tbcd-induced microtubule destruction
70	induces cell cycle arrest, reduces ability to form microtubules and centrosome fragmentation. inhibits the interaction w
76	does not reduce interaction with arl2bp.
80	reduces interaction with arl2bp.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-389977	Post-chaperonin tubulin folding pathway
R-HSA-83936	Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane
R-HSA-9648002	RAS processing
R-HSA-162582	Signal Transduction
R-HSA-382551	Transport of small molecules
R-HSA-391251	Protein folding
R-HSA-392499	Metabolism of proteins
R-HSA-425397	Transport of vitamins, nucleosides, and related molecules
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling

MSigDB gene sets: 272 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION

GO Biological Process (10): regulation of glycolytic process (GO:0006110), protein folding (GO:0006457), centrosome cycle (GO:0007098), positive regulation of cell-substrate adhesion (GO:0010811), regulation of microtubule polymerization (GO:0031113), positive regulation of microtubule polymerization (GO:0031116), negative regulation of GTPase activity (GO:0034260), maintenance of protein location in nucleus (GO:0051457), bicellular tight junction assembly (GO:0070830), regulation of aerobic respiration (GO:1903715)

GO Molecular Function (5): GTPase activity (GO:0003924), GTP binding (GO:0005525), GDP binding (GO:0019003), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (15): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758), mitochondrial matrix (GO:0005759), centrosome (GO:0005813), centriole (GO:0005814), cytosol (GO:0005829), microtubule cytoskeleton (GO:0015630), lateral plasma membrane (GO:0016328), ciliary basal body (GO:0036064), sperm midpiece (GO:0097225), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Protein folding	1
Transport of vitamins, nucleosides, and related molecules	1
RAF/MAP kinase cascade	1
Metabolism of proteins	1
SLC-mediated transmembrane transport	1
Transport of small molecules	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
intracellular membraneless organelle	3
microtubule organizing center	3
microtubule polymerization	2
guanyl ribonucleotide binding	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
cytoplasm	2
glycolytic process	1
regulation of purine nucleotide catabolic process	1
regulation of generation of precursor metabolites and energy	1
regulation of carbohydrate catabolic process	1
regulation of ATP metabolic process	1
cellular process	1
protein maturation	1
cell cycle process	1
microtubule organizing center organization	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
positive regulation of cell adhesion	1
regulation of microtubule polymerization or depolymerization	1
regulation of protein polymerization	1
regulation of supramolecular fiber organization	1
positive regulation of microtubule polymerization or depolymerization	1
regulation of microtubule polymerization	1
positive regulation of protein polymerization	1
positive regulation of supramolecular fiber organization	1
GTPase activity	1
regulation of GTPase activity	1
negative regulation of biological process	1
negative regulation of hydrolase activity	1
nucleus	1
protein localization to nucleus	1
maintenance of protein localization in organelle	1
apical junction assembly	1
tight junction assembly	1
aerobic respiration	1
regulation of cellular respiration	1
ribonucleoside triphosphate phosphatase activity	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

989 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARL2	UNC119	Q13432	903
ARL2	TBCD	Q9BTW9	835
ARL2	ARL2BP	Q9Y2Y0	803
ARL2	RPGR	Q92834	681
ARL2	ELMOD2	Q8IZ81	653
ARL2	TBCC	Q15814	624
ARL2	TBCB	Q99426	620
ARL2	HCK	P08631	591
ARL2	IL5RA	Q01344	570
ARL2	ELMOD1	Q8N336	569
ARL2	A0A2R8Y809	A0A2R8Y809	564
ARL2	TBCE	Q15813	564
ARL2	PDE6D	O43924	553
ARL2	RHEB	Q15382	553
ARL2	UNC119B	A6NIH7	548

IntAct

132 interactions, top by confidence:

A	B	Type	Score
ARL2BP	ARL2	psi-mi:“MI:0915”(physical association)	0.970
ARL2	ARL2BP	psi-mi:“MI:0915”(physical association)	0.970
ARL2BP	ARL2	psi-mi:“MI:0407”(direct interaction)	0.970
ARL2	ARL2BP	psi-mi:“MI:2364”(proximity)	0.970
ARL2	PDE6D	psi-mi:“MI:0915”(physical association)	0.960
PDE6D	ARL2	psi-mi:“MI:0915”(physical association)	0.960
ARL2	PDE6D	psi-mi:“MI:0407”(direct interaction)	0.960
PDE6D	ARL2	psi-mi:“MI:0407”(direct interaction)	0.960

BioGRID (188): PDE6D (Two-hybrid), UNC119 (Two-hybrid), ARL2BP (Two-hybrid), TBL1XR1 (Two-hybrid), ARL2 (Affinity Capture-RNA), ARL2 (Affinity Capture-MS), ARL2 (Affinity Capture-MS), ARL2 (Affinity Capture-MS), PDE6D (Two-hybrid), ARL2 (Co-fractionation), ARL2 (Proximity Label-MS), PDE6D (Two-hybrid), ARL2BP (Reconstituted Complex), ARL2BP (Reconstituted Complex), ARL2 (Reconstituted Complex)

ESM2 similar proteins: A8ISN6, B5FYQ0, O08697, O48649, O48920, P0CM16, P0CM17, P0DH91, P36397, P36404, P36405, P37996, P40617, P40940, P49076, P51821, P51822, P51823, P61213, P61214, Q06396, Q06849, Q19705, Q1MTE5, Q2KI07, Q2TA37, Q2TBW6, Q3T0M9, Q4R4S4, Q52NJ4, Q54R04, Q5R6E7, Q5ZKQ8, Q627K4, Q66HA6, Q6NZW8, Q6P8C8, Q8QHI3, Q8VEH3, Q8VY57

Diamond homologs: A8INQ0, A8ISN6, B5FYQ0, O04266, O04834, O08697, O23778, O45379, O48649, O48920, P0CM16, P0CM17, P0DH91, P11076, P19146, P20606, P22274, P26990, P26991, P36397, P36404, P36405, P36579, P37996, P38116, P40616, P40940, P40945, P40946, P49076, P51643, P51645, P51821, P51822, P51823, P51824, P61204, P61205, P61206, P61207

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	7	61.4×	1e-09
Transport of connexons to the plasma membrane	7	61.4×	1e-09
Gap junction trafficking and regulation	7	53.7×	2e-09
Gap junction trafficking	7	53.7×	2e-09
Post-chaperonin tubulin folding pathway	7	53.7×	2e-09
RHO GTPases activate IQGAPs	8	44.6×	1e-09
Activation of AMPK downstream of NMDARs	7	43.0×	8e-09
HCMV Infection	8	42.1×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
microtubule cytoskeleton organization	10	15.3×	5e-07
mitotic cell cycle	8	13.5×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

30 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	24
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
983502	NM_001667.4(ARL2):c.44G>T (p.Arg15Leu)	Pathogenic

SpliceAI

1197 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65018471:GAGG:G	donor_gain	1.0000
11:65018473:GG:G	donor_gain	1.0000
11:65018474:GG:G	donor_gain	1.0000
11:65018569:A:AG	acceptor_gain	1.0000
11:65018570:G:GA	acceptor_gain	1.0000
11:65018730:GGAG:G	donor_gain	1.0000
11:65018731:G:GT	donor_gain	1.0000
11:65018731:GAGG:G	donor_loss	1.0000
11:65018732:AGG:A	donor_loss	1.0000
11:65018733:GG:G	donor_loss	1.0000
11:65018734:G:GA	donor_loss	1.0000
11:65020417:A:AG	acceptor_gain	1.0000
11:65020418:G:GG	acceptor_gain	1.0000
11:65020418:GC:G	acceptor_gain	1.0000
11:65020418:GCGC:G	acceptor_gain	1.0000
11:65020418:GCGCC:G	acceptor_gain	1.0000
11:65020498:AGG:A	donor_loss	1.0000
11:65020499:GGT:G	donor_loss	1.0000
11:65020500:G:GA	donor_loss	1.0000
11:65020501:T:A	donor_loss	1.0000
11:65021717:CCA:C	acceptor_loss	1.0000
11:65021718:CAG:C	acceptor_loss	1.0000
11:65021718:CAGGT:C	acceptor_loss	1.0000
11:65021719:A:AG	acceptor_gain	1.0000
11:65021720:G:GA	acceptor_gain	1.0000
11:65021720:GGTC:G	acceptor_gain	1.0000
11:65021848:C:G	donor_gain	1.0000
11:65014252:G:GT	donor_gain	0.9900
11:65014270:GCT:G	donor_gain	0.9900
11:65014284:G:GT	donor_gain	0.9900

AlphaMissense

1201 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65018383:A:C	K29Q	1.000
11:65018446:T:C	F50L	1.000
11:65018448:C:A	F50L	1.000
11:65018448:C:G	F50L	1.000
11:65020457:G:C	K126N	1.000
11:65020457:G:T	K126N	1.000
11:65018365:G:C	G23R	0.999
11:65018380:G:A	G28R	0.999
11:65018380:G:C	G28R	0.999
11:65018381:G:A	G28E	0.999
11:65018381:G:T	G28V	0.999
11:65018383:A:G	K29E	0.999
11:65018384:A:C	K29T	0.999
11:65018384:A:T	K29M	0.999
11:65018385:G:C	K29N	0.999
11:65018385:G:T	K29N	0.999
11:65018387:C:T	T30I	0.999
11:65018443:G:C	G49R	0.999
11:65018444:G:A	G49D	0.999
11:65018447:T:C	F50S	0.999
11:65018587:T:A	W65R	0.999
11:65018587:T:C	W65R	0.999
11:65018589:G:C	W65C	0.999
11:65018589:G:T	W65C	0.999
11:65018590:G:C	D66H	0.999
11:65018591:A:C	D66A	0.999
11:65018591:A:G	D66G	0.999
11:65018591:A:T	D66V	0.999
11:65018597:G:A	G68D	0.999
11:65018599:G:C	G69R	0.999

dbSNP variants (sampled 300 via entrez): RS1000042185 (11:65014790 T>G), RS1000117241 (11:65016641 CCCTGTGTGTG>C), RS1000221831 (11:65017768 T>C), RS1000278734 (11:65022366 C>T), RS1000366738 (11:65020891 G>A,T), RS1000647835 (11:65016290 G>C), RS1000707187 (11:65022093 A>C,G,T), RS1000956240 (11:65016676 T>G), RS1001300035 (11:65017043 C>T), RS1001533496 (11:65017837 A>G), RS1001557400 (11:65012640 C>T), RS1001705776 (11:65018093 T>C), RS1001757902 (11:65017913 G>A), RS1002050402 (11:65012368 T>G), RS1002152395 (11:65016770 G>C,T)

Disease associations

OMIM: gene MIM:601175 | disease phenotypes: MIM:619082

GenCC curated gene-disease

Disease	Classification	Inheritance
microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1	Strong	Autosomal dominant

Mondo (1): microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1 (MONDO:0033644)

Orphanet (0):

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000482	Microcornea
HP:0000510	Rod-cone dystrophy
HP:0000518	Cataract
HP:0003577	Congenital onset
HP:0007663	Reduced visual acuity
HP:0030856	Posterior staphyloma

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295751 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
FR900359	increases phosphorylation	1
bisphenol A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CD 437	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	affects expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Arbutin	decreases expression	1
Vehicle Emissions	affects expression, increases abundance	1
Doxorubicin	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Paraquat	decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression, affects cotreatment	1
Valproic Acid	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	affects expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119003	Binding	Binding affinity to ARL2 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.