ARL3

Chr 10ARAD

ARF like GTPase 3

Also known as: ARFL3, JBTS35, RP83

NCBI Gene: 403ENSG00000138175UniProt: P36405

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. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Joubert syndrome 35MIM #618161
AR
Retinitis pigmentosa 83MIM #618173
AD
186
ClinVar variants
21
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ARL3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
21 Pathogenic / Likely Pathogenic· 96 VUS of 186 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.10LOEUF
pLI 0.001
Z-score 1.35
OE 0.56 (0.30–1.10)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.16Z-score
OE missense 0.67 (0.55–0.82)
65 obs / 97.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.56 (0.30–1.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.55–0.82)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 6 / 10.8Missense obs/exp: 65 / 97.1Syn Z: 0.14

ClinVar Variant Classifications

186 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic1
VUS96
Likely Benign50
Benign3
Conflicting5
20
Pathogenic
1
Likely Pathogenic
96
VUS
50
Likely Benign
3
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
18
0
20
Likely Pathogenic
0
0
1
0
1
VUS
9
63
22
2
96
Likely Benign
0
1
24
25
50
Benign
0
0
2
1
3
Conflicting
—5
Total9666728175

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

View in ClinVar →

Protein Context — Lollipop Plot

ARL3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ARL3-related Joubert syndrome

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

ARL3-related retinitis pigmentosa

limited
ADUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Joubert syndrome 35

MIM #618161

Molecular basis of disorder known

Autosomal recessive

Retinitis pigmentosa 83

MIM #618173

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dominant ARL3-related retinitis pigmentosa.
Holtan JP et al.·Ophthalmic Genet
2019
Disrupting the ciliary gradient of active Arl3 affects rod photoreceptor nuclear migration.
Travis AM et al.·Elife
2023
A novel recurrent ARL3 variant c.209G > A p.(Gly70Glu) causes variable non-syndromic dominant retinal dystrophy with defective lipidated protein transport in human retinal stem cell models.
Corral-Serrano JC et al.·Hum Mol Genet
2025Functional
Homozygous Variant in ARL3 Causes Autosomal Recessive Cone Rod Dystrophy.
Sheikh SA et al.·Invest Ophthalmol Vis Sci
2019
Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease.
Dueñas Rey A et al.·Genome Med
2024Functional
Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development.
Powell L et al.·BMC Dev Biol
2020
N(6) -methyladenosine modification of circular RNA circ-ARL3 facilitates Hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305.
Rao X et al.·IUBMB Life
2021
Piperine inhibits the proliferation of colorectal adenocarcinoma by regulating ARL3-mediated endoplasmic reticulum stress.
Wu C et al.·Biomol Biomed
2025
De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa.
Strom SP et al.·PLoS One
2016Case report
ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition.
Alkanderi S et al.·Am J Hum Genet
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools