ARL6

protein-coding

ADP ribosylation factor like GTPase 6, the group of ARF GTPase family

Gene summary

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). [provided by RefSeq, Apr 2016]

Previous symbols:

BBS3

MANE transcript

NM_001278293.3

Inheritance

AR, AD

ClinVar variants

P:56U:83B:57

Top phenotype

Bardet-Biedl syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr3:97,764,521-97,801,229

External References & Databases

Ensembl (ENSG00000113966)

Transcript & Mutation Effects

hg38 • Region Span ~36.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*ARL6* (OMIM: 608845), located at 3p12, encodes the ADP-ribosylation factor-like protein 6, a small GTPase that functions as a molecular switch. In its active, GTP-bound state, *ARL6* recruits the BBSome complex to the primary cilium, which is required for trafficking membrane proteins essential for ciliary signaling and maintenance (PMID: 20603001, 20207729). Multiple independent reports have identified biallelic pathogenic variants in *ARL6* in patients with classic Bardet-Biedl (BBS) features such as retinal dystrophy, obesity, polydactyly, renal anomalies, and cognitive involvement. Based on the ClinGen Lumping and Splitting Working Group criteria, this disease presents on a spectrum from syndromic Bardet-Biedl syndrome 3 (BBS3; MONDO:0010832) to non-syndromic retinitis pigmentosa 55 (RP55; MONDO:0013312); these were lumped and curated under “ciliopathy” (MONDO:0005308) because of a shared molecular mechanism and overlapping phenotypes. The mechanism is biallelic loss-of-function, resulting in disrupted ciliary transport and subsequent pleiotropic phenotypes. The gene-disease relationship is supported by genetic evidence (12/12 points) from multiple independent cohorts, including nonsense, frameshift, missense, and large deletion variants (PMIDs: 15258860, 15314642, 32361989, 31736247, 27486776). Segregation evidence includes a LOD score of 9.85 in a large Bedouin kindred with a homozygous nonsense variant (p.Arg122Ter) (PMIDs: 7987310, 15258860). The relationship is also supported by experimental evidence (6/6 points). Functional studies demonstrate that pathogenic missense variants are unstable and degraded by the proteasome (PMID: 19236846), and that *ARL6* modulates Wnt signaling (PMID: 20207729). A Bbs3-knockout mouse model recapitulates key BBS phenotypes including retinal degeneration and male infertility (PMID: 22139371). Furthermore, rescue experiments in zebrafish demonstrate that the systemic (BBS3) and eye-specific (BBS3L) isoforms have distinct functions that explain the syndromic versus non-syndromic presentations (PMID: 20333246). In summary, there is definitive evidence supporting the relationship between *ARL6* and autosomal recessive ciliopathies. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on July 14th, 2025 (SOP Version 11).

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Bardet-Biedl syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Bardet-Biedl syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010832

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 55STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013312

Submitter: G2P

Bardet-Biedl syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010832

Submitter: Genomics England PanelApp

Bardet-Biedl syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010832

Submitter: G2P

ciliopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: PanelApp Australia

retinitis pigmentosa 55STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013312

Submitter: Labcorp Genetics (formerly Invitae)

Bardet-Biedl syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010832

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Bardet-Biedl syndrome 3AR

Manifestation: Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular; Endocrine

Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial

Comments: Variants may modify the severity of BBS due to variants in other BBS-associated genes

Refs: 7987310; 9714014; 15258860; 15314642; 19956407; 19858128; 20301537; 23219996; 36356613

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARL6 variants in ClinVar

15 Conditions Cataloged

Bardet-Biedl syndrome 3Total: 218

Retinitis pigmentosa 55Total: 211

ARL6-related disorderTotal: 58

Bardet-Biedl syndrome 1Total: 35

not providedTotal: 29

Inborn genetic diseasesTotal: 20

Retinitis pigmentosaTotal: 17

Retinal dystrophyTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001278293.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar		55 clinvar		56
missense	6 clinvar	14 clinvar	77 clinvar	2 clinvar		99
nonsense	9 clinvar	3 clinvar	1 clinvar			13
start loss	1 clinvar					1
frameshift	6 clinvar	2 clinvar	3 clinvar			11
splice donor/acceptor (+/-2bp)	4 clinvar	10 clinvar	2 clinvar			16
Total	26	30	83	57	0	196

Highest pathogenic variant AF is 0.0000179824

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001278293.3	RefSeq	NP_001265222.1	7	MANE Select
ENST00000463745.6	Ensembl	ENSP00000419619.1	7	MANE Select
NM_001323513.2	RefSeq	NP_001310442.1	8	Standard
NM_001323514.2	RefSeq	NP_001310443.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
arl6	Danio rerio	Structure: whole organism Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

arl6

Danio rerio

Structure: whole organism

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

BBSome-mediated cargo-targeting to cilium
Cargo trafficking to the periciliary membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

protein targeting to membrane
intracellular protein transport
determination of left/right symmetry
brain development
visual perception

Molecular Function

protein binding
GTP binding
phospholipid binding
metal ion binding

Cellular Component

cytoplasm
cytosol
axonemal microtubule
plasma membrane
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000463745
Coding exons: 7
Length: 36589
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125729
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.555	81	96.3	0.841	0.00000460	1228
Missense (PolyPhen)		22	32.632	0.67418		425
Synonymous	0.176	32	33.3	0.961	0.00000164	332
Loss of Function	1.77	5	11.5	0.436	5.47e-7	148

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (PubMed:20603001). Together with BBS1, is necessary for correct trafficking of PKD1 to primary cilia (By similarity). Together with the BBSome complex and LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation (PubMed:22072986). May regulate cilia assembly and disassembly and subsequent ciliary signaling events such as the Wnt signaling cascade (PubMed:20207729). Isoform 2 may be required for proper retinal function and organization (By similarity). {ECO:0000250|UniProtKB:O88848, ECO:0000269|PubMed:20207729, ECO:0000269|PubMed:20603001, ECO:0000269|PubMed:22072986}.;
Disease: DISEASE: Bardet-Biedl syndrome 3 (BBS3) [MIM:600151]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. 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. {ECO:0000269|PubMed:15258860, ECO:0000269|PubMed:15314642, ECO:0000269|PubMed:23219996}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:19956407}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.208

Intolerance Scores

LoFtool: 0.310
RVIS EVS: -0.1
RVIS percentile EVS: 46.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium