ARL3

Summary

ARL3 (ARF like GTPase 3, HGNC:694) is a protein-coding gene on chromosome 10q24.32, encoding ADP-ribosylation factor-like protein 3 (P36405). 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).

Enables GDP binding activity; GTP binding activity; and microtubule binding activity. Involved in several processes, including cilium assembly; protein localization to cilium; and small GTPase-mediated signal transduction. Acts upstream of or within post-Golgi vesicle-mediated transport. Located in several cellular components, including microtubule cytoskeleton; midbody; and photoreceptor connecting cilium. Implicated in Joubert syndrome and retinitis pigmentosa 83.

Source: NCBI Gene 403 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Joubert syndrome 35 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 165 total — 3 pathogenic
• Phenotypes (HPO): 89
• MANE Select transcript: NM_004311

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:694
Approved symbol	ARL3
Name	ARF like GTPase 3
Location	10q24.32
Locus type	gene with protein product
Status	Approved
Aliases	ARFL3
Ensembl gene	ENSG00000138175
Ensembl biotype	protein_coding
OMIM	604695
Entrez	403

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000260746, ENST00000901818, ENST00000901819, ENST00000901820, ENST00000901821, ENST00000901822, ENST00000901823, ENST00000901824, ENST00000920806

RefSeq mRNA: 1 — MANE Select: NM_004311 NM_004311

CCDS: CCDS7538

Canonical transcript exons

ENST00000260746 — 6 exons

Exon	Start	End
ENSE00000933227	102699373	102699489
ENSE00000933228	102689893	102689943
ENSE00001026242	102673731	102676941
ENSE00001026243	102685816	102686001
ENSE00001304265	102714273	102714397
ENSE00001319100	102705346	102705489

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.5980 / max 389.0836, expressed in 1814 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111190	24.3796	1812
111189	6.1817	1620
111188	1.9511	1069
111187	0.0856	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	98.09	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.98	gold quality
epithelium of bronchus	UBERON:0002031	97.56	gold quality
bronchus	UBERON:0002185	97.43	gold quality
palpebral conjunctiva	UBERON:0001812	96.71	gold quality
eye	UBERON:0000970	96.66	gold quality
pigmented layer of retina	UBERON:0001782	96.53	gold quality
retina	UBERON:0000966	96.51	gold quality
pons	UBERON:0000988	96.38	gold quality
substantia nigra pars compacta	UBERON:0001965	96.19	gold quality
adult organism	UBERON:0007023	96.03	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.95	gold quality
tibia	UBERON:0000979	95.91	gold quality
epithelium of nasopharynx	UBERON:0001951	95.88	gold quality
nasopharynx	UBERON:0001728	95.86	gold quality
lateral globus pallidus	UBERON:0002476	95.70	gold quality
orbitofrontal cortex	UBERON:0004167	95.46	gold quality
choroid plexus epithelium	UBERON:0003911	95.36	gold quality
trigeminal ganglion	UBERON:0001675	95.25	gold quality
caput epididymis	UBERON:0004358	95.11	gold quality
superior vestibular nucleus	UBERON:0007227	95.10	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.01	gold quality
middle temporal gyrus	UBERON:0002771	94.94	gold quality
ventral tegmental area	UBERON:0002691	94.90	gold quality
renal medulla	UBERON:0000362	94.81	gold quality
periodontal ligament	UBERON:0008266	94.70	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.61	gold quality
nephron tubule	UBERON:0001231	94.60	gold quality
corpus epididymis	UBERON:0004359	94.58	gold quality
cortical plate	UBERON:0005343	94.58	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	15.31
E-MTAB-9388	no	8.14
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

111 targeting ARL3, 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-4262	100.00	73.26	3931
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-589-3P	99.91	69.62	2088
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-7162-3P	99.89	68.16	1682
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-576-5P	99.84	70.46	2582

Literature-anchored findings (GeneRIF, showing 23)

• Knockdown of Arl3 by siRNA resulted in changes in cell morphology, increased acetylation of alpha-tubulin, failure of cytokinesis, and increased number of binucleated cells. (PMID:16525022)
• Arl2 and Arl3 interactions were characterized. (PMID:18588884)
• We propose that RP2 regulation of Arl3 is important for maintaining Golgi cohesion, facilitating the transport and docking of vesicles and thereby carrying proteins to the base of the photoreceptor connecting cilium for transport to the outer segment. (PMID:20106869)
• The G proteins Arl3 acts in a GTP-dependent manner as allosteric release factors for farnesylated cargo. (PMID:22002721)
• When Arl3 binds UNC119, it allosterically displaces cargo by accelerating its release by 3 orders of magnitude. The N-terminal amphipathic helix of Arl3.GppNHp is not displaced by the interswitch toggle but remains bound on the surface of the protein. (PMID:22960633)
• Arl3 acts negatively in ciliogenesis but positively in cilia signaling (Review). (PMID:23548655)
• this study identifies ARL3 as a key player in prenylated protein trafficking in rod photoreceptor cells and establishes the potential role for ARL3 dysregulation in the pathogenesis of RP2-related forms of XLRP (PMID:26936825)
• De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa. (PMID:26964041)
• These results indicate that ARL3 interacts with STAT3 and regulates the transcriptional activation of STAT3 by influencing its nuclear accumulation of STAT3. (PMID:27048653)
• Novel Biochemical and Structural Insights into the Interaction of Myristoylated Cargo with Unc119 Protein and Their Release by Arl2/3. (PMID:27481943)
• Studies indicate that the binding of UNC119 and PDE6D, to the lipid-modified ciliary cargo and the specific release of the cargo in the cilia by the ciliary small G-protein Arl3 in a GTP-dependent manner. (PMID:27911709)
• Biochemical characterization of purified mammalian ARL13B protein indicates that it is an atypical GTPase and ARL3 guanine nucleotide exchange factor (GEF).( (PMID:28487361)
• We utilized a structure-based approach to pinpoint the binding interface to a strictly conserved cluster of residues on the surface of RP2 that spans both the C- and N-terminal domains of the protein, and which is structurally distinct from the ARL3-binding site.RP2 is a positive regulator of cell motility in vitro, recruiting OSTF1 to the cell membrane and preventing its interaction with the migration regulator Myo1E. (PMID:29361551)
• By molecular functional analysis, we observed that ARL3 promotes the aggregation of GFP-LC3, up-regulation of LC3-II/LC3-I and down-regulation of SQSMT1/BECN1, and knocking down of ARL3 inbibits autophagy, which suggested that ARL3 is necessary for autophagy. (PMID:30227171)
• ARL3 provides a potential hub in the network of proteins implicated in ciliopathies. (PMID:30269812)
• Our study confirms that the ARL3 missense variant p.(Tyr90Cys) causes retinitis pigmentosa. (PMID:30932721)
• Low ARL3 expression predicted poor prognosis and contributed to antiangiogenesis and the proportion of infiltrating immune cells in the GBM microenvironment. Thus, ARL3 may be a prognostic marker and therapeutic target for glioma. (PMID:31234870)
• Our study uncovers an additional cone rod dystrophy (CRD) gene and assigns the CRD phenotype to a variant of ARL3. The results imply that cargo transportation in photoreceptors as mediated by the ARL3 pathway is essential for cone and rod cell survival and vision in humans. (PMID:31743939)
• Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development. (PMID:33297941)
• ARL3 activation requires the co-GEF BART and effector-mediated turnover. (PMID:33438581)
• Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials. (PMID:34208932)
• Human Mutations in Arl3, a Small GTPase Involved in Lipidated Cargo Delivery to the Cilia, Cause Retinal Dystrophy. (PMID:37440046)
• Mechanisms underlying morphological and functional changes of cilia in fibroblasts derived from patients bearing ARL3[T31A] and ARL3[T31A/C118F] mutations. (PMID:38457249)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	arl3a	ENSDARG00000056794
danio_rerio	arl3b	ENSDARG00000071409
mus_musculus	Arl3	ENSMUSG00000025035
rattus_norvegicus	Arl3	ENSRNOG00000019973

Paralogs (30): ARF5 (ENSG00000004059), SAR1A (ENSG00000079332), ARFRP1 (ENSG00000101246), TRIM23 (ENSG00000113595), ARL6 (ENSG00000113966), ARL1 (ENSG00000120805), ARL4A (ENSG00000122644), ARL8B (ENSG00000134108), ARF3 (ENSG00000134287), 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), ARL2 (ENSG00000213465), ARL16 (ENSG00000214087), ARL17B (ENSG00000228696)

Protein

Protein identifiers

ADP-ribosylation factor-like protein 3 — P36405 (reviewed: P36405)

All UniProt accessions (1): P36405

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). Required for normal cytokinesis and cilia signaling. Requires assistance from GTPase-activating proteins (GAPs) like RP2 and PDE6D, in order to cycle between inactive GDP-bound and active GTP-bound forms. Required for targeting proteins to the cilium, including myristoylated NPHP3 and prenylated INPP5E. Targets NPHP3 to the ciliary membrane by releasing myristoylated NPHP3 from UNC119B cargo adapter into the cilium. Required for PKD1:PKD2 complex targeting from the trans-Golgi network to the cilium.

Subunit / interactions. Found in a complex with ARL3, RP2 and UNC119 (or UNC119B); RP2 induces hydrolysis of GTP ARL3 in the complex, leading to the release of UNC119 (or UNC119B). Interacts with RP2; interaction is direct and stimulated with the activated GTP-bound form of ARL3. Interacts with SYS1. The GTP-bound form interacts with ARL2BP and PDE6D. Microtubule-associated protein. May interact with GOLGA4. Interacts with GGA1; the interaction recruits PKD1:PKD2 complex to trans-Golgi network and is required for ciliary targeting of PKD1:PKD2 complex. Interacts with DNAAF9.

Subcellular location. Golgi apparatus membrane. Cytoplasm. Cytoskeleton. Spindle. Nucleus. Microtubule organizing center. Centrosome. Cell projection. Cilium.

Tissue specificity. Expressed in the retina. Strongly expressed in connecting cilium, the myoid region of the inner segments (IS) and in cone photoreceptors (at protein level).

Disease relevance. Joubert syndrome 35 (JBTS35) [MIM:618161] A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS35 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa 83 (RP83) [MIM:618173] An autosomal dominant form of retinitis pigmentosa, a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease may be caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_004302* (*=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

Pfam: PF00025

UniProt features (18 total): binding site 8, sequence variant 4, mutagenesis site 2, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36405-F1	92.73	0.85

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 (8): 24–31; 31; 48; 48; 67–71; 70; 126–129; 159–161

Post-translational modifications (2): 5, 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
31	enhances the interaction with rp2.
71	enhances the interaction with rp2. does not induce a mitotic arrest resulting from the loss of the microtubule-based mit

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5624138	Trafficking of myristoylated proteins to the cilium
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-5617833	Cilium Assembly
R-HSA-5620920	Cargo trafficking to the periciliary membrane

MSigDB gene sets: 467 (showing top): GOBP_MITOTIC_CYTOKINESIS, RNGTGGGC_UNKNOWN, MORF_FLT1, DORSAM_HOXA9_TARGETS_UP, TGCGCANK_UNKNOWN, MORF_MSH3, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, MORF_BRCA1, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, AP2_Q3, MORF_ESR1, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, MORF_RAD51L3, GOCC_MICROTUBULE_ORGANIZING_CENTER

GO Biological Process (14): mitotic cytokinesis (GO:0000281), kidney development (GO:0001822), post-Golgi vesicle-mediated transport (GO:0006892), Golgi to plasma membrane transport (GO:0006893), smoothened signaling pathway (GO:0007224), small GTPase-mediated signal transduction (GO:0007264), protein transport (GO:0015031), intraciliary transport (GO:0042073), photoreceptor cell development (GO:0042461), cilium assembly (GO:0060271), protein localization to cilium (GO:0061512), protein localization to ciliary membrane (GO:1903441), G protein-coupled receptor signaling pathway (GO:0007186), cell division (GO:0051301)

GO Molecular Function (10): magnesium ion binding (GO:0000287), GTPase activity (GO:0003924), GTP binding (GO:0005525), microtubule binding (GO:0008017), GDP binding (GO:0019003), nucleotide binding (GO:0000166), protein binding (GO:0005515), guanyl nucleotide binding (GO:0019001), G-protein beta/gamma-subunit complex binding (GO:0031683), metal ion binding (GO:0046872)

GO Cellular Component (19): Golgi membrane (GO:0000139), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), centrosome (GO:0005813), spindle microtubule (GO:0005876), cytoplasmic microtubule (GO:0005881), cilium (GO:0005929), microtubule cytoskeleton (GO:0015630), midbody (GO:0030496), photoreceptor connecting cilium (GO:0032391), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), extracellular exosome (GO:0070062), spindle (GO:0005819), cytoskeleton (GO:0005856), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cargo trafficking to the periciliary membrane	1
Organelle biogenesis and maintenance	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cilium	3
cilium organization	2
protein localization to cilium	2
guanyl ribonucleotide binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
microtubule organizing center	2
microtubule	2
intracellular membraneless organelle	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
animal organ development	1
renal system development	1
Golgi vesicle transport	1
post-Golgi vesicle-mediated transport	1
vesicle-mediated transport to the plasma membrane	1
cell surface receptor signaling pathway	1
intracellular signaling cassette	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
transport along microtubule	1
photoreceptor cell differentiation	1
neuron development	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
protein localization to organelle	1
protein localization to membrane	1
protein localization to cell periphery	1
G protein-coupled receptor activity	1
signal transduction	1
cellular process	1
metal ion binding	1
ribonucleoside triphosphate phosphatase activity	1

Protein interactions and networks

STRING

2494 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARL3	RASA1	P20936	872
ARL3	SYS1	Q8N2H4	867
ARL3	UNC119	Q13432	866
ARL3	TBCC	Q15814	865
ARL3	UNC119B	A6NIH7	758
ARL3	CFAP36	Q96G28	754
ARL3	PDE6D	O43924	727
ARL3	RPGR	Q92834	689
ARL3	CDKN2A	P42771	687
ARL3	RABEP1	Q15276	656
ARL3	IFT20	Q8IY31	649
ARL3	IFT27	Q9BW83	649
ARL3	IFT88	Q13099	647
ARL3	ELMOD2	Q8IZ81	644
ARL3	NPHP3	Q7Z494	636
ARL3	SCOC	Q9UIL1	636

IntAct

59 interactions, top by confidence:

A	B	Type	Score
ARL3	UNC119	psi-mi:“MI:0915”(physical association)	0.940
UNC119	ARL3	psi-mi:“MI:0407”(direct interaction)	0.940
UNC119	ARL2	psi-mi:“MI:0914”(association)	0.920
PDE6D	ARL3	psi-mi:“MI:0914”(association)	0.920
PDE6D	ARL3	psi-mi:“MI:0915”(physical association)	0.920
PDE6D	ARL3	psi-mi:“MI:0407”(direct interaction)	0.920
ARL2BP	ARL3	psi-mi:“MI:0915”(physical association)	0.840
ARL3	ARL2BP	psi-mi:“MI:0915”(physical association)	0.840
ARL3	UNC119B	psi-mi:“MI:0914”(association)	0.730
UNC119	UNC119B	psi-mi:“MI:0914”(association)	0.640
ARL3	RP2	psi-mi:“MI:0915”(physical association)	0.620
ARL3	RP2	psi-mi:“MI:0914”(association)	0.620
TBL1X	ARL3	psi-mi:“MI:0915”(physical association)	0.560
ARL3	BSND	psi-mi:“MI:0407”(direct interaction)	0.440
RP1L1	ARL3	psi-mi:“MI:0407”(direct interaction)	0.440
ARL3	TBCD	psi-mi:“MI:0407”(direct interaction)	0.440
ARL3		psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
ARL3	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
ARL2BP	GNPAT	psi-mi:“MI:0914”(association)	0.350
PDE6D	SUN1	psi-mi:“MI:0914”(association)	0.350
PDE6D	UBL3	psi-mi:“MI:0914”(association)	0.350

BioGRID (98): ARL3 (Affinity Capture-MS), ARL3 (Synthetic Growth Defect), ARL3 (Affinity Capture-MS), UNC119 (Affinity Capture-MS), ARL3 (Affinity Capture-MS), ARL3 (Affinity Capture-MS), ARL3 (Affinity Capture-MS), UNC119B (Affinity Capture-MS), ARL3 (Affinity Capture-MS), ESF1 (Affinity Capture-MS), WRN (Affinity Capture-MS), ARL3 (Affinity Capture-MS), ARL3 (Affinity Capture-MS), RP2 (Reconstituted Complex), ARL3 (Two-hybrid)

ESM2 similar proteins: A8ISN6, B5FYQ0, O00909, O45379, O48649, O48920, P0CM16, P0CM17, P0DH91, P18085, P25160, P36397, P36405, P37996, P38116, P40616, P40940, P49076, P49702, P51644, P51821, P56559, P61208, P61211, P61212, P61750, P61751, P84081, P84082, P84083, P84084, P84085, Q06396, Q19705, Q1MTE5, Q20758, Q2TBW6, Q2YDM1, Q3SZF2, Q52NJ4

Diamond homologs: A6NH57, B5FYQ0, O00909, O23778, O48649, O48920, P0CM16, P0CM17, P0DH91, P11076, P18085, P19146, P22274, P25160, P26990, P26991, P34212, P34727, P36397, P36405, P36406, P36407, P36579, P37996, P38116, P40616, P40940, P40945, P40946, P40994, P49076, P49702, P51643, P51644, P51645, P51646, P51821, P51822, P51823, P51824

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	95
Likely benign	47
Benign	3

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1460216	NC_000010.10:g.(?104262628)(104595248_?)del	Pathogenic
587372	NM_004311.4(ARL3):c.445C>T (p.Arg149Cys)	Pathogenic
617788	NM_004311.4(ARL3):c.296G>T (p.Arg99Ile)	Pathogenic

SpliceAI

879 predictions. Top by Δscore:

Variant	Effect	Δscore
10:102686001:CCTG:C	acceptor_loss	1.0000
10:102686003:T:A	acceptor_loss	1.0000
10:102686009:T:C	acceptor_gain	1.0000
10:102686009:T:TC	acceptor_gain	1.0000
10:102689888:TTTA:T	donor_loss	1.0000
10:102689890:TACC:T	donor_loss	1.0000
10:102689891:A:T	donor_loss	1.0000
10:102689939:TATAT:T	acceptor_gain	1.0000
10:102689941:TAT:T	acceptor_gain	1.0000
10:102689941:TATC:T	acceptor_loss	1.0000
10:102689944:C:A	acceptor_loss	1.0000
10:102689944:C:CC	acceptor_gain	1.0000
10:102689945:T:C	acceptor_loss	1.0000
10:102699367:ACTT:A	donor_loss	1.0000
10:102699368:CT:C	donor_loss	1.0000
10:102699369:TTACA:T	donor_loss	1.0000
10:102699370:TA:T	donor_loss	1.0000
10:102699371:A:AC	donor_gain	1.0000
10:102699371:ACAAG:A	donor_loss	1.0000
10:102699372:C:CT	donor_gain	1.0000
10:102699372:CA:C	donor_gain	1.0000
10:102699372:CAA:C	donor_gain	1.0000
10:102699372:CAAG:C	donor_gain	1.0000
10:102699372:CAAGA:C	donor_gain	1.0000
10:102699486:AACC:A	acceptor_gain	1.0000
10:102699487:ACC:A	acceptor_gain	1.0000
10:102699488:CC:C	acceptor_gain	1.0000
10:102699488:CCC:C	acceptor_gain	1.0000
10:102699489:CC:C	acceptor_gain	1.0000
10:102699490:C:A	acceptor_loss	1.0000

AlphaMissense

1194 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:102699484:G:C	F51L	1.000
10:102699484:G:T	F51L	1.000
10:102699486:A:G	F51L	1.000
10:102685936:C:A	K127N	0.999
10:102685936:C:G	K127N	0.999
10:102699437:T:G	D67A	0.999
10:102699438:C:G	D67H	0.999
10:102705401:G:A	T31I	0.999
10:102705403:C:A	K30N	0.999
10:102705403:C:G	K30N	0.999
10:102705404:T:A	K30M	0.999
10:102705405:T:G	K30Q	0.999
10:102705407:C:T	G29D	0.999
10:102685937:T:G	K127T	0.998
10:102685938:T:C	K127E	0.998
10:102685943:G:T	A125D	0.998
10:102685952:A:G	L122P	0.998
10:102699428:C:T	G70E	0.998
10:102699431:C:T	G69D	0.998
10:102699437:T:A	D67V	0.998
10:102699437:T:C	D67G	0.998
10:102699441:A:G	W66R	0.998
10:102699441:A:T	W66R	0.998
10:102699485:A:G	F51S	0.998
10:102699489:C:G	G50R	0.998
10:102705404:T:G	K30T	0.998
10:102705405:T:C	K30E	0.998
10:102705423:C:G	G24R	0.998
10:102685937:T:A	K127M	0.997
10:102685939:A:C	N126K	0.997

dbSNP variants (sampled 300 via entrez): RS1000019408 (10:102692504 C>T), RS1000072202 (10:102679834 C>T), RS1000290733 (10:102706400 C>T), RS1000296649 (10:102713312 A>G), RS1000322523 (10:102713698 A>G), RS1000358183 (10:102680027 CT>C), RS1000363348 (10:102680862 C>A,T), RS1000456039 (10:102685196 C>A), RS1000516035 (10:102687671 G>C), RS1000674534 (10:102693620 G>T), RS1000708123 (10:102681427 T>G), RS1000734928 (10:102700310 G>A), RS1000821832 (10:102698674 G>A), RS1000890927 (10:102707611 A>T), RS1000966567 (10:102678589 C>T)

Disease associations

OMIM: gene MIM:604695 | disease phenotypes: MIM:618161, MIM:618173, MIM:109400, MIM:155255, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 83	Strong	Autosomal dominant
Joubert syndrome 35	Strong	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant
Joubert syndrome	Supportive	Autosomal recessive

Mondo (7): Joubert syndrome 35 (MONDO:0032570), retinitis pigmentosa 83 (MONDO:0032577), inherited retinal dystrophy (MONDO:0019118), nevoid basal cell carcinoma syndrome (MONDO:0007187), medulloblastoma (MONDO:0007959), retinitis pigmentosa (MONDO:0019200), Joubert syndrome (MONDO:0018772)

Orphanet (4): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Gorlin syndrome (Orphanet:377), Medulloblastoma (Orphanet:616), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000126	Hydronephrosis
HP:0000202	Orofacial cleft
HP:0000238	Hydrocephalus
HP:0000276	Long face
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000612	Iris coloboma
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001942_1	Prostate cancer	5.000000e-10
GCST002539_4	Schizophrenia	6.000000e-19
GCST003880_9	Schizophrenia	3.000000e-09
GCST004257_1	Systolic blood pressure (long-term average)	3.000000e-08
GCST004259_1	Mean arterial pressure (long-term average)	3.000000e-08
GCST004521_172	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_53	Autism spectrum disorder or schizophrenia	9.000000e-10
GCST004946_86	Schizophrenia	4.000000e-20
GCST005956_50	Waist-to-hip ratio adjusted for BMI	8.000000e-06
GCST005958_15	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06
GCST005962_36	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-07
GCST006585_988	Blood protein levels	4.000000e-19
GCST007703_138	Systolic blood pressure	5.000000e-11
GCST007704_106	Diastolic blood pressure	2.000000e-06
GCST007705_65	Pulse pressure	2.000000e-07
GCST007706_96	Mean arterial pressure	2.000000e-09
GCST009600_73	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-09
GCST010002_298	Refractive error	3.000000e-22
GCST010703_271	Brain morphology (MOSTest)	5.000000e-13
GCST012227_619	Hip circumference adjusted for BMI	1.000000e-08
GCST90020029_148	Waist circumference adjusted for body mass index	2.000000e-14

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0004346	neuroimaging measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001478	Basal Cell Nevus Syndrome	C04.182.089.530.690.150; C04.557.470.200.165.150; C04.557.470.565.165.150; C04.700.175; C05.116.099.105; C05.500.470.690.150; C07.320.450.670.130; C16.131.077.130; C16.320.700.175
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	2
Smoke	decreases expression, increases abundance, increases expression	2
Genistein	increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenate	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, increases reaction	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
ochratoxin A	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
hydroquinone	decreases expression	1
beta-methylcholine	affects expression	1
nutlin 3	affects cotreatment, increases secretion	1
dorsomorphin	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT02875314	PHASE4	ACTIVE_NOT_RECRUITING	HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00049959	PHASE3	TERMINATED	Two Studies to Determine if Verteporfin PDT is Effective & Safe in Treating Multiple Basal Cell Carcinoma of the Skin.
NCT03703310	PHASE3	COMPLETED	Study of Patidegib Topical Gel, 2%, for the Reduction of Disease Burden of Persistently Developing Basal Cell Carcinomas (BCCs) in Subjects With Basal Cell Nevus Syndrome (Gorlin Syndrome)
NCT04308395	PHASE3	TERMINATED	Extension Study of Patidegib Topical Gel, 2% in Subjects With Gorlin Syndrome (Basal Cell Nevus Syndrome)
NCT06050122	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Patidegib Gel 2% for Preventing Basal Cell Carcinomas on the Face of Adults With Gorlin Syndrome
NCT00085735	PHASE3	COMPLETED	Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma
NCT00336024	PHASE3	COMPLETED	Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma
NCT00392327	PHASE3	ACTIVE_NOT_RECRUITING	Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma/PNET
NCT01351870	PHASE3	COMPLETED	Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma (PNET4)
NCT07291102	PHASE3	NOT_YET_RECRUITING	Comparison of Neurocognitive Outcome in Two Standard Regimen for Treatment of Low-risk Medulloblastoma
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)