ARL6

Chr 3ARDigenic recessive

ARF like GTPase 6

Also known as: BBS3, RP55

NCBI Gene: 84100 ENSG00000113966 UniProt: Q9H0F7 OMIM: 608845

The protein regulates membrane protein trafficking to primary cilia and controls assembly of the BBSome complex, which is essential for proper ciliary function and signaling pathways including sonic hedgehog and Wnt. Mutations cause Bardet-Biedl syndrome, a multisystem ciliopathy affecting vision, kidney function, obesity, and intellectual development, as well as isolated retinitis pigmentosa. Inheritance is autosomal recessive.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/Digenic recessiveLOEUF 0.923 OMIM phenotypes

Clinical Summary— ARL6

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Gene-Disease Validity (ClinGen)

ciliopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

59 unique Pathogenic / Likely Pathogenic· 102 VUS of 310 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ARL6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.010

Z-score 1.77

OE 0.44 (0.23–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.56Z-score

OE missense 0.84 (0.70–1.01)

81 obs / 96.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.23–0.92)

0≤0.351.4

Missense OE?0.84 (0.70–1.01)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 5 / 11.5Missense obs/exp: 81 / 96.3Syn Z: 0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveARL6-related Bardet-Biedl syndromeLOFAR

strongARL6-related retinal dystrophyOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.78top 25%

GOF

0.72top 25%

LOF

0.2679th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

310 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31

Likely Pathogenic28

VUS102

Likely Benign119

Benign11

Conflicting10

Pathogenic

Likely Pathogenic

102

VUS

119

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	6	6	0	31
Likely Pathogenic	14	10	3	1	28
VUS	4	78	20	0	102
Likely Benign	0	3	65	51	119
Benign	0	0	11	0	11
Conflicting	—				10
Total	37	97	105	52	301

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap ARL6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →