ARL6

Summary

ARL6 (ARF like GTPase 6, HGNC:13210) is a protein-coding gene on chromosome 3q11.2, encoding ADP-ribosylation factor-like protein 6 (Q9H0F7). Involved in membrane protein trafficking at the base of the ciliary organelle.

The protein encoded by this gene belongs to the ARF-like (ADP ribosylation factor-like) sub-family of the ARF family of GTP-binding proteins which are involved in regulation of intracellular traffic. Mutations in this gene are associated with Bardet-Biedl syndrome (BBS). A vision-specific transcript, encoding long isoform BBS3L, has been described (PMID: 20333246).

Source: NCBI Gene 84100 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ciliopathy (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 322 total — 31 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 161
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001278293

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13210
Approved symbol	ARL6
Name	ARF like GTPase 6
Location	3q11.2
Locus type	gene with protein product
Status	Approved
Aliases	RP55
Ensembl gene	ENSG00000113966
Ensembl biotype	protein_coding
OMIM	608845
Entrez	84100

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000335979, ENST00000462412, ENST00000463745, ENST00000476753, ENST00000493990, ENST00000494363, ENST00000496713, ENST00000631834, ENST00000857055, ENST00000935545

RefSeq mRNA: 5 — MANE Select: NM_001278293 NM_001278293, NM_001323513, NM_001323514, NM_032146, NM_177976

CCDS: CCDS2928, CCDS93329

Canonical transcript exons

ENST00000463745 — 8 exons

Exon	Start	End
ENSE00000817855	97791771	97791826
ENSE00001844797	97798024	97801229
ENSE00001857631	97764758	97764977
ENSE00003498931	97787990	97788119
ENSE00003565387	97768081	97768230
ENSE00003572177	97780159	97780220
ENSE00003616259	97784955	97785049
ENSE00003656348	97780615	97780683

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 91.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2619 / max 666.9594, expressed in 1680 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37511	9.8650	1637
37509	1.8392	1007
37510	0.2232	84
37512	0.1526	58
37513	0.1469	46
202852	0.0350	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	91.31	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.67	gold quality
endothelial cell	CL:0000115	90.37	gold quality
middle temporal gyrus	UBERON:0002771	88.68	gold quality
sperm	CL:0000019	87.33	gold quality
bronchial epithelial cell	CL:0002328	87.06	gold quality
bronchus	UBERON:0002185	85.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.28	gold quality
oocyte	CL:0000023	85.27	gold quality
prefrontal cortex	UBERON:0000451	85.02	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.01	gold quality
right uterine tube	UBERON:0001302	84.79	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.72	gold quality
primary visual cortex	UBERON:0002436	84.55	gold quality
cortical plate	UBERON:0005343	84.21	gold quality
islet of Langerhans	UBERON:0000006	84.11	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.82	gold quality
frontal cortex	UBERON:0001870	83.04	gold quality
neocortex	UBERON:0001950	82.81	gold quality
nucleus accumbens	UBERON:0001882	82.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.42	gold quality
cerebral cortex	UBERON:0000956	82.32	gold quality
caudate nucleus	UBERON:0001873	82.18	gold quality
anterior cingulate cortex	UBERON:0009835	81.85	gold quality
calcaneal tendon	UBERON:0003701	81.71	gold quality
occipital lobe	UBERON:0002021	81.67	gold quality
right frontal lobe	UBERON:0002810	81.61	gold quality
putamen	UBERON:0001874	81.51	gold quality
fallopian tube	UBERON:0003889	81.30	gold quality
forebrain	UBERON:0001890	81.17	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting ARL6, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-5187-5P	98.54	67.94	952
HSA-MIR-548S	98.50	67.17	1213
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-10395-3P	98.10	66.70	1726
HSA-MIR-6728-5P	97.79	66.33	891
HSA-MIR-630	97.50	66.38	921
HSA-MIR-1226-5P	96.50	65.28	643
HSA-MIR-6834-5P	96.25	64.88	823
HSA-MIR-6734-5P	95.70	65.56	950

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 16)

• We uncovered four different homozygous substitutions in ARL6 in four unrelated families affected with Bardet-Biedl syndrome, two of which disrupt a threonine residue important for GTP binding and function of several related small GTP-binding proteins. (PMID:15314642)
• These findings implicate that Arl6 mutants are destabilized and eliminated by the proteasome in cells, probably due to the altered nucleotide-binding properties. (PMID:19236846)
• the first null mutation reported in BBS3 gene in patient with Bardet-Biedl syndrome (PMID:20142850)
• Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. (PMID:20207729)
• These data demonstrate that the BBS3L transcript is required for proper retinal function and organization. (PMID:20333246)
• BBS3 A89V is sufficient to rescue the transport delays induced by the loss of BBS3 but was unable to rescue vision impairment (PMID:21282186)
• Mutations identified in the present study extend the body of evidence implicating the genes ARL6 and BBS10 in causing Bardet-Biedl syndrome. (PMID:23219996)
• Arl6 is indispensable in cilia signaling but dispensable in ciliogenesis (Review). (PMID:23548655)
• Results show that BBS1 and BBS3 regulates the ciliary traficking of PC1. (PMID:24939912)
• The BBSome is a coat-like ciliary trafficking complex composed of proteins mutated in Bardet-Biedl syndrome. ARL6 E108A mutation prevents BBSome recruitment to cilia. (PMID:25402481)
• Elevated levels of serum ARL6 were able to discriminate between excessive alcohol users and controls. (PMID:25704570)
• Mutations of the ARL6 gene cause Bardet-Biedl syndrome, a heterogeneous disorder that increases the risk of Hypertension and Diabetes mellitus. (PMID:27271309)
• In the 64 BBS patients (44 males, 20 females) were studied, mutations were predominant in BBS10 and ARL6 genes; the c.272T>C; p.(I91T) mutation in ARL6 gene was a recurrent mutation (PMID:29806606)
• Structure and activation mechanism of the BBSome membrane protein trafficking complex. (PMID:31939736)
• High prevalence of Bardet-Biedl syndrome in La Reunion Island is due to a founder variant in ARL6/BBS3. (PMID:32361989)
• The Prognostic and Therapeutic Roles of ARL-6 Gene in Hepatocellular Carcinoma. (PMID:38169538)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	arl6	ENSDARG00000032056
mus_musculus	Arl6	ENSMUSG00000022722
rattus_norvegicus	Arl6	ENSRNOG00000001689
drosophila_melanogaster	Arl6	FBGN0034446
caenorhabditis_elegans		WBGENE00000193

Paralogs (30): ARF5 (ENSG00000004059), SAR1A (ENSG00000079332), ARFRP1 (ENSG00000101246), TRIM23 (ENSG00000113595), 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), ARL2 (ENSG00000213465), ARL16 (ENSG00000214087), ARL17B (ENSG00000228696)

Protein

Protein identifiers

ADP-ribosylation factor-like protein 6 — Q9H0F7 (reviewed: Q9H0F7)

Alternative names: Bardet-Biedl syndrome 3 protein

All UniProt accessions (4): Q9H0F7, A0A0J9YXT0, C9IZ13, H7C5H6

UniProt curated annotations — full annotation on UniProt →

Function. Involved in membrane protein trafficking at the base of the ciliary organelle. Mediates recruitment onto plasma membrane of the BBSome complex which would constitute a coat complex required for sorting of specific membrane proteins to the primary cilia. Together with BBS1, is necessary for correct trafficking of PKD1 to primary cilia. Together with the BBSome complex and LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. May regulate cilia assembly and disassembly and subsequent ciliary signaling events such as the Wnt signaling cascade. Isoform 2 may be required for proper retinal function and organization.

Subunit / interactions. Interacts with SEC61B, ARL6IP1, ARL6IP2, ARL6IP3, ARL6IP4 ARL6IP5 and ARL6IP6. Interacts (GTP-bound form) with the BBSome a complex that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts (GTP-free form) with IFT27.

Subcellular location. Cell projection. Cilium membrane. Cytoplasm. Cytoskeleton. Cilium axoneme. Cilium basal body.

Disease relevance. Bardet-Biedl syndrome 3 (BBS3) [MIM:600151] A syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and intellectual disability. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa 55 (RP55) [MIM:613575] 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 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?
Q9H0F7-1	1, BBS3	yes
Q9H0F7-2	2, BBS3L

RefSeq proteins (5): NP_001265222, NP_001310442, NP_001310443, NP_115522, NP_816931 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005225	Small_GTP-bd	Domain
IPR006689	Small_GTPase_ARF/SAR	Family
IPR024156	Small_GTPase_ARF	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041839	Arl6	Family

Pfam: PF00025

UniProt features (34 total): binding site 8, helix 7, sequence variant 6, strand 6, turn 3, initiator methionine 1, chain 1, lipid moiety-binding region 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2H57	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0F7-F1	94.81	0.88

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; 50; 50; 69–73; 72; 130–133; 164

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5620922	BBSome-mediated cargo-targeting to 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: 448 (showing top): GOBP_PIGMENT_GRANULE_LOCALIZATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_VESICLE_LOCALIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, AAGCCAT_MIR135A_MIR135B, GOBP_PROTEIN_TARGETING, GOBP_CELLULAR_PIGMENTATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_NEURAL_RETINA_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_PIGMENTATION, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_PROTEIN_TARGETING_TO_MEMBRANE

GO Biological Process (18): protein targeting to membrane (GO:0006612), intracellular protein transport (GO:0006886), determination of left/right symmetry (GO:0007368), brain development (GO:0007420), visual perception (GO:0007601), regulation of smoothened signaling pathway (GO:0008589), retina layer formation (GO:0010842), Wnt signaling pathway (GO:0016055), vesicle-mediated transport (GO:0016192), melanosome transport (GO:0032402), fat cell differentiation (GO:0045444), protein polymerization (GO:0051258), cilium assembly (GO:0060271), protein localization to cilium (GO:0061512), protein localization to non-motile cilium (GO:0097499), protein transport from ciliary membrane to plasma membrane (GO:1903445), protein transport (GO:0015031), cell projection organization (GO:0030030)

GO Molecular Function (6): GTPase activity (GO:0003924), GTP binding (GO:0005525), phospholipid binding (GO:0005543), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (14): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), axonemal microtubule (GO:0005879), plasma membrane (GO:0005886), cilium (GO:0005929), axoneme (GO:0005930), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), membrane coat (GO:0030117), extracellular exosome (GO:0070062), cytoskeleton (GO:0005856), cell projection (GO:0042995), ciliary membrane (GO:0060170)

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
intracellular protein localization	2
transport	2
protein localization to cilium	2
cytoplasm	2
cytoskeleton	2
protein targeting	1
establishment of protein localization to membrane	1
protein transport	1
intracellular transport	1
determination of bilateral symmetry	1
left/right pattern formation	1
central nervous system development	1
animal organ development	1
head development	1
sensory perception of light stimulus	1
smoothened signaling pathway	1
regulation of signal transduction	1
neural retina development	1
anatomical structure formation involved in morphogenesis	1
retina morphogenesis in camera-type eye	1
cell surface receptor signaling pathway	1
cellular process	1
melanosome localization	1
establishment of melanosome localization	1
pigment granule transport	1
cell differentiation	1
protein-containing complex assembly	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	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 transport within lipid bilayer	1
establishment of protein localization to plasma membrane	1
protein localization to plasma membrane	1
establishment of protein localization	1

Protein interactions and networks

STRING

1749 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARL6	BBS1	Q8NFJ9	596
ARL6	ARL6IP5	O75915	555
ARL6	ARL6IP1	Q15041	483
ARL6	TTC8	Q8TAM2	391
ARL6	BBS7	Q8IWZ6	374
ARL6	C2orf80	Q0P641	370
ARL6	BBS5	Q8N3I7	364
ARL6	BBS12	Q6ZW61	358
ARL6	IFT27	Q9BW83	351
ARL6	BBS9	P78514	344
ARL6	WDPCP	O95876	341
ARL6	CFAP418	Q96NL8	340
ARL6	BBS10	Q8TAM1	340
ARL6	BBS2	Q9BXC9	335
ARL6	PKHD1	P08F94	333

IntAct

26 interactions, top by confidence:

A	B	Type	Score
ARL6	BBS1	psi-mi:“MI:0914”(association)	0.650
ARL6	BBS1	psi-mi:“MI:0403”(colocalization)	0.650
ARL6	BBS1	psi-mi:“MI:0915”(physical association)	0.650
ARL6	SART1	psi-mi:“MI:0914”(association)	0.510
	ARL6	psi-mi:“MI:0915”(physical association)	0.400
ARL6	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400
ARL6		psi-mi:“MI:0914”(association)	0.350
ARL6	BBS4	psi-mi:“MI:0914”(association)	0.350
SBNO1	HSPA2	psi-mi:“MI:0914”(association)	0.350
ARL6	AMPD2	psi-mi:“MI:0914”(association)	0.350
ARL6	BBS7	psi-mi:“MI:0914”(association)	0.350
ARL6	BBS9	psi-mi:“MI:0403”(colocalization)	0.350
BBIP1	ARL6	psi-mi:“MI:0403”(colocalization)	0.270
ARL6	SART1	psi-mi:“MI:0915”(physical association)	0.000
TOR1AIP2	ARL6	psi-mi:“MI:0915”(physical association)	0.000
RREB1	ARL6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (36): ARL6 (Affinity Capture-MS), ARL6 (Affinity Capture-MS), SART1 (Affinity Capture-MS), SEC61B (Affinity Capture-Western), ARL6IP5 (Two-hybrid), ARL6IP4 (Two-hybrid), ARL6IP1 (Two-hybrid), ATL2 (Two-hybrid), ARL6IP6 (Two-hybrid), AMPD2 (Affinity Capture-MS), KLHL42 (Affinity Capture-MS), ARL6 (Affinity Capture-MS), NEDD8-MDP1 (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), CCT8 (Proximity Label-MS)

ESM2 similar proteins: A4D1S5, A6NH57, O45379, O59781, O88848, P25160, P25378, P34212, P38116, P40994, P51152, P51646, Q02804, Q0IIM2, Q13795, Q18510, Q2KJ96, Q32LJ2, Q3SXC5, Q54E92, Q54HK2, Q54I24, Q54JJ3, Q54V41, Q54V47, Q54Y14, Q54YV7, Q55AD9, Q5JT25, Q5M9P8, Q5R4G5, Q5R579, Q5RCQ6, Q60Z38, Q61DE0, Q63055, Q6P068, Q6P3A9, Q80ZU0, Q8BXL7

Diamond homologs: A8ISN6, B5FYQ0, O00909, O23778, O45379, O48649, O48920, O88848, P0CM16, P0CM17, P0DH91, P11076, P18085, P19146, P22274, P25160, P26990, P26991, P34727, P36397, P36405, P36406, P36407, P36579, P37996, P38116, P40940, P40945, P40946, P40994, P49076, P49702, P51643, P51644, P51645, P51646, P51821, P51822, P51823, P51824

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 12 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.

GO biological processes:

GO term	Partners	Fold	FDR
cilium assembly	5	30.7×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	24
Uncertain significance	113
Likely benign	116
Benign	11

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075539	NM_001278293.3(ARL6):c.4G>T (p.Gly2Ter)	Pathogenic
1076146	NC_000003.11:g.(?97194196)(97510809_?)del	Pathogenic
1297538	NM_001278293.3(ARL6):c.185+1G>A	Pathogenic
1446585	NM_001278293.3(ARL6):c.1A>G (p.Met1Val)	Pathogenic
1457182	NC_000003.11:g.(?97498983)(97516893_?)del	Pathogenic
1459992	NC_000003.11:g.(?97486952)(97516893_?)del	Pathogenic
2040	NM_001278293.3(ARL6):c.364C>T (p.Arg122Ter)	Pathogenic
2042	NM_001278293.3(ARL6):c.92C>T (p.Thr31Met)	Pathogenic
2043	NM_001278293.3(ARL6):c.509T>G (p.Leu170Trp)	Pathogenic
2071999	NM_001278293.3(ARL6):c.469del (p.Trp157fs)	Pathogenic
2102573	NM_001278293.3(ARL6):c.262C>T (p.Gln88Ter)	Pathogenic
2115026	NM_001278293.3(ARL6):c.127C>T (p.Gln43Ter)	Pathogenic
2498296	NM_001278293.3(ARL6):c.302G>T (p.Arg101Ile)	Pathogenic
2501015	NC_000003.11:g.(97487075_97499002)(97520087?)del	Pathogenic
2920654	NM_001278293.3(ARL6):c.377T>G (p.Leu126Ter)	Pathogenic
2940871	NM_001278293.3(ARL6):c.228C>A (p.Tyr76Ter)	Pathogenic
2942834	NM_001278293.3(ARL6):c.406_409del (p.Asp136fs)	Pathogenic
2943163	NM_001278293.3(ARL6):c.188T>A (p.Leu63Ter)	Pathogenic
2950730	NM_001278293.3(ARL6):c.66C>A (p.Cys22Ter)	Pathogenic
2950809	NM_001278293.3(ARL6):c.252T>G (p.Tyr84Ter)	Pathogenic
3069201	NM_001278293.3(ARL6):c.255-2A>T	Pathogenic
3246908	NC_000003.11:g.(?97486952)(97487094_?)del	Pathogenic
3250156	NM_001278293.3(ARL6):c.186-2A>C	Pathogenic
3381780	NM_001278293.3(ARL6):c.387_394del (p.Asn130fs)	Pathogenic
370033	NM_001278293.3(ARL6):c.351_353delinsGAAAA (p.Asp117fs)	Pathogenic
576069	NM_001278293.3(ARL6):c.185+1G>C	Pathogenic
813156	NM_001278293.3(ARL6):c.528G>T (p.Trp176Cys)	Pathogenic
827585	NM_001278293.3(ARL6):c.535G>A (p.Asp179Asn)	Pathogenic
832088	NC_000003.12:g.(?97768108)(97768230_?)del	Pathogenic
861499	NM_001278293.3(ARL6):c.506del (p.Gly169fs)	Pathogenic

SpliceAI

1714 predictions. Top by Δscore:

Variant	Effect	Δscore
3:97768079:A:AG	acceptor_gain	1.0000
3:97768079:AGCT:A	acceptor_gain	1.0000
3:97768080:G:GG	acceptor_gain	1.0000
3:97768080:GCTG:G	acceptor_gain	1.0000
3:97768228:AAT:A	donor_gain	1.0000
3:97768228:AATG:A	donor_loss	1.0000
3:97768229:AT:A	donor_gain	1.0000
3:97768230:TGTA:T	donor_loss	1.0000
3:97768231:G:GG	donor_gain	1.0000
3:97768231:GTAAG:G	donor_loss	1.0000
3:97768232:TAAGT:T	donor_loss	1.0000
3:97768233:AAGTA:A	donor_loss	1.0000
3:97768234:AGTAT:A	donor_loss	1.0000
3:97780613:A:AG	acceptor_gain	1.0000
3:97780614:G:GA	acceptor_gain	1.0000
3:97780614:GT:G	acceptor_gain	1.0000
3:97780614:GTT:G	acceptor_gain	1.0000
3:97780614:GTTT:G	acceptor_gain	1.0000
3:97780683:AG:A	donor_loss	1.0000
3:97780684:G:GG	donor_gain	1.0000
3:97780685:TA:T	donor_loss	1.0000
3:97780686:AA:A	donor_loss	1.0000
3:97787989:GAT:G	acceptor_gain	1.0000
3:97764974:CCAG:C	donor_loss	0.9900
3:97764975:CAGGT:C	donor_loss	0.9900
3:97764976:AG:A	donor_loss	0.9900
3:97764977:GG:G	donor_loss	0.9900
3:97764978:G:GA	donor_loss	0.9900
3:97764979:T:A	donor_loss	0.9900
3:97768073:A:AG	acceptor_gain	0.9900

AlphaMissense

1229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:97788032:A:T	K131I	0.999
3:97768196:A:T	K30I	0.998
3:97768171:T:C	C22R	0.996
3:97768193:G:A	G29D	0.996
3:97768195:A:C	K30Q	0.996
3:97780667:T:A	W80R	0.996
3:97780667:T:C	W80R	0.996
3:97780669:G:C	W80C	0.996
3:97780669:G:T	W80C	0.996
3:97784986:A:C	S96R	0.996
3:97784988:T:A	S96R	0.996
3:97784988:T:G	S96R	0.996
3:97788033:A:C	K131N	0.996
3:97788033:A:T	K131N	0.996
3:97791821:T:C	L177P	0.996
3:97784978:T:A	V93D	0.995
3:97785026:T:C	L109P	0.995
3:97788109:T:A	W157R	0.995
3:97788109:T:C	W157R	0.995
3:97791775:A:C	S162R	0.995
3:97791777:T:A	S162R	0.995
3:97791777:T:G	S162R	0.995
3:97768177:G:A	G24R	0.994
3:97768177:G:C	G24R	0.994
3:97785002:G:C	R101T	0.994
3:97788032:A:C	K131T	0.994
3:97791817:T:A	W176R	0.994
3:97791817:T:C	W176R	0.994
3:97768166:T:A	V20D	0.993
3:97768189:A:C	S28R	0.993

dbSNP variants (sampled 300 via entrez): RS1000017559 (3:97785679 A>T), RS1000104881 (3:97788797 T>C), RS1000121994 (3:97798854 G>A,T), RS1000305652 (3:97798431 C>T), RS1000308403 (3:97781545 T>A), RS1000420319 (3:97796582 T>C), RS1000438810 (3:97775315 A>G), RS1000489069 (3:97790734 T>C,G), RS1000564909 (3:97785596 T>C), RS1000580058 (3:97793220 C>G), RS1000702402 (3:97778471 A>G), RS1000788233 (3:97785875 T>C), RS1000834651 (3:97784140 G>A), RS1000960064 (3:97769619 C>A,G), RS1001108254 (3:97764476 C>A,T)

Disease associations

OMIM: gene MIM:608845 | disease phenotypes: MIM:600151, MIM:613575, MIM:209900, MIM:268000, MIM:120970

GenCC curated gene-disease

Disease	Classification	Inheritance
Bardet-Biedl syndrome 3	Definitive	Autosomal recessive
retinitis pigmentosa 55	Strong	Autosomal recessive
ciliopathy	Strong	Autosomal recessive
Bardet-Biedl syndrome	Supportive	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ciliopathy	Definitive	AR

Mondo (9): Bardet-Biedl syndrome 3 (MONDO:0010832), retinitis pigmentosa 55 (MONDO:0013312), Bardet-Biedl syndrome 1 (MONDO:0008854), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), optic atrophy (MONDO:0003608), cone-rod dystrophy (MONDO:0015993), Bardet-Biedl syndrome (MONDO:0015229), ciliopathy (MONDO:0005308)

Orphanet (4): Bardet-Biedl syndrome (Orphanet:110), Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cone rod dystrophy (Orphanet:1872)

HPO phenotypes

161 total (30 of 161 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000085	Horseshoe kidney
HP:0000089	Renal hypoplasia
HP:0000100	Nephrotic syndrome
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000137	Abnormality of the ovary
HP:0000147	Polycystic ovaries
HP:0000148	Vaginal atresia
HP:0000163	Abnormal oral cavity morphology
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000388	Otitis media
HP:0000400	Macrotia
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000470	Short neck

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000412_2	Male infertility	7.000000e-07

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C537909	Bardet-Biedl syndrome 1 (supp.)
C537911	Bardet-Biedl syndrome 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cadmium	decreases expression, decreases reaction, increases abundance, increases expression	2
Smoke	increases abundance, increases expression, decreases expression	2
Valproic Acid	increases expression	2
Cadmium Chloride	decreases expression, decreases reaction, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
CGP 52608	affects binding, increases reaction	1
clothianidin	increases expression	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Estradiol	affects expression	1
Potassium Dichromate	decreases expression	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

288 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
NCT03746522	PHASE3	COMPLETED	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
NCT04966741	PHASE3	COMPLETED	Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
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
NCT03490019	PHASE2	WITHDRAWN	Treatment of Bardet-Biedl-Syndrome With Metformin for Evaluation of a Possible Visual Improvement
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)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)