Joubert syndrome 8

Summary

Joubert syndrome 8 (MONDO:0012855) is a disease caused by ARL13B (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: ARL13B (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 349

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 8
Mondo ID	MONDO:0012855
MeSH	C567358
OMIM	612291
DOID	DOID:0111003
UMLS	C2676771
MedGen	436772
GARD	0015550
Is cancer (heuristic)	no

Also known as: ARL13B Joubert syndrome · JBTS8 · Joubert syndrome 8 · Joubert syndrome caused by mutation in ARL13B · Joubert syndrome type 8

Data availability: 349 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome › Joubert syndrome 8

Related subtypes (38): Joubert syndrome 1, Joubert syndrome 10, Joubert syndrome 2, Joubert syndrome 3, Joubert syndrome with renal defect, Joubert syndrome 5, Joubert syndrome 6, Joubert syndrome 7, Joubert syndrome 9, Joubert syndrome 13, Joubert syndrome 14, Joubert syndrome 15, Joubert syndrome 16, Joubert syndrome 17, Joubert syndrome 18, Joubert syndrome 20, Joubert syndrome 21, Joubert syndrome 22, Joubert syndrome 23, Joubert syndrome 24, Joubert syndrome 25, Joubert syndrome 26, Joubert syndrome 27, Joubert syndrome 28, Joubert syndrome 38, Joubert syndrome 39, Joubert syndrome 40, Joubert syndrome 37, Joubert syndrome 35, Joubert syndrome 36, Joubert syndrome 30, Joubert syndrome 32, Joubert syndrome 31, Joubert syndrome 33, Joubert syndrome 19, Joubert syndrome 29, Joubert syndrome 11, Joubert syndrome 34

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

349 retrieved; paginated sample, class counts are floors:

151 uncertain significance, 130 likely benign, 23 conflicting classifications of pathogenicity, 15 pathogenic, 11 likely pathogenic, 10 pathogenic/likely pathogenic, 6 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076313	NM_001174150.2(ARL13B):c.986dup (p.Asn330fs)	ARL13B	Pathogenic	criteria provided, single submitter
1370150	NM_001174150.2(ARL13B):c.440dup (p.Ser148fs)	ARL13B	Pathogenic	criteria provided, single submitter
1418737	NM_001174150.2(ARL13B):c.554G>A (p.Trp185Ter)	ARL13B	Pathogenic	criteria provided, single submitter
1440955	NM_001174150.2(ARL13B):c.772C>T (p.Gln258Ter)	ARL13B	Pathogenic	criteria provided, single submitter
1453361	NM_001174150.2(ARL13B):c.932dup (p.Asn311fs)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1896131	NM_001174150.2(ARL13B):c.830del (p.Asn277fs)	ARL13B	Pathogenic	criteria provided, single submitter
1991	NM_001174150.2(ARL13B):c.236G>A (p.Arg79Gln)	ARL13B	Pathogenic	no assertion criteria provided
1992	NM_001174150.2(ARL13B):c.246G>A (p.Trp82Ter)	ARL13B	Pathogenic	criteria provided, single submitter
1993	NM_001174150.2(ARL13B):c.598C>T (p.Arg200Cys)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2035764	NM_001174150.2(ARL13B):c.538A>T (p.Lys180Ter)	ARL13B	Pathogenic	criteria provided, single submitter
2176910	NM_001174150.2(ARL13B):c.550del (p.Tyr184fs)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203408	NM_001174150.2(ARL13B):c.223G>A (p.Gly75Arg)	ARL13B	Pathogenic	criteria provided, multiple submitters, no conflicts
2427601	NC_000003.11:g.(?93714775)(93724716_?)del	ARL13B	Pathogenic	criteria provided, single submitter
266096	NM_001174150.2(ARL13B):c.599G>A (p.Arg200His)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736786	NM_001174150.2(ARL13B):c.73_74del (p.Leu25fs)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
285657	NM_001174150.2(ARL13B):c.131-1G>T	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3013775	NM_001174150.2(ARL13B):c.709C>T (p.Gln237Ter)	ARL13B	Pathogenic	criteria provided, single submitter
3246903	NC_000003.11:g.(?93754155)(93755618_?)del	ARL13B	Pathogenic	criteria provided, single submitter
3589671	NM_001174150.2(ARL13B):c.861C>A (p.Cys287Ter)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589679	NM_001174150.2(ARL13B):c.1147dup (p.Trp383fs)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3672046	NM_001174150.2(ARL13B):c.679C>T (p.Arg227Ter)	ARL13B	Pathogenic	criteria provided, single submitter
4716798	NM_001174150.2(ARL13B):c.977del (p.Gln326fs)	ARL13B	Pathogenic	criteria provided, single submitter
4764779	NM_001174150.2(ARL13B):c.822_823del (p.Asn277fs)	ARL13B	Pathogenic	criteria provided, single submitter
578346	NM_001174150.2(ARL13B):c.393_396del (p.Gln132fs)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631931	NM_001174150.2(ARL13B):c.830dup (p.Asn277fs)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068135	NM_001174150.2(ARL13B):c.689+2T>G	ARL13B	Likely pathogenic	criteria provided, single submitter
2053319	NM_001174150.2(ARL13B):c.1141+1G>A	ARL13B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589653	NM_001174150.2(ARL13B):c.51del (p.Glu17fs)	ARL13B	Likely pathogenic	criteria provided, single submitter
3589657	NM_001174150.2(ARL13B):c.381-1G>A	ARL13B	Likely pathogenic	criteria provided, single submitter
3589658	NM_001174150.2(ARL13B):c.402_405del (p.Gly136fs)	ARL13B	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ARL13B	Definitive	Autosomal recessive	Joubert syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARL13B	Orphanet:475	Isolated Joubert syndrome
PROS1	Orphanet:743	Severe hereditary thrombophilia due to congenital protein S deficiency

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARL13B	HGNC:25419	ENSG00000169379	Q3SXY8	ADP-ribosylation factor-like protein 13B	gencc,clinvar
STX19	HGNC:19300	ENSG00000178750	Q8N4C7	Syntaxin-19	clinvar
NSUN3	HGNC:26208	ENSG00000178694	Q9H649	tRNA (cytosine(34)-C(5))-methyltransferase, mitochondrial	clinvar
DHFR2	HGNC:27309	ENSG00000178700	Q86XF0	Dihydrofolate reductase 2, mitochondrial	clinvar
PROS1	HGNC:9456	ENSG00000184500	P07225	Vitamin K-dependent protein S	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARL13B	ADP-ribosylation factor-like protein 13B	Cilium-specific protein required to control the microtubule-based, ciliary axoneme structure.
STX19	Syntaxin-19	Plays a role in endosomal trafficking of the epidermal growth factor receptor (EGFR).
NSUN3	tRNA (cytosine(34)-C(5))-methyltransferase, mitochondrial	Mitochondrial tRNA methyltransferase that mediates methylation of cytosine to 5-methylcytosine (m5C) at position 34 of mt-tRNA(Met). mt-tRNA(Met) methylation at cytosine(34) takes place at the wobble position of the anticodon and initiates…
DHFR2	Dihydrofolate reductase 2, mitochondrial	Key enzyme in folate metabolism.
PROS1	Vitamin K-dependent protein S	Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	4.8×	0.117
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARL13B	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, P-loop_NTPase
STX19	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
NSUN3	Enzyme (other)	yes	2.1.1.203	MeTrfase_RsmB-F_NOP2_dom, RCMT, SAM-dependent_MTases_sf
DHFR2	Enzyme (other)	yes	1.5.1.3	DHFR_dom, DHFR, DHFR-like_dom_sf
PROS1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, GLA_domain, EGF

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	2
calcaneal tendon	2
secondary oocyte	1
esophagus squamous epithelium	1
mucosa of transverse colon	1
rectum	1
male germ cell	1
sperm	1
buccal mucosa cell	1
kidney epithelium	1
pancreatic ductal cell	1
choroid plexus epithelium	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARL13B	237	ubiquitous	marker	secondary oocyte, calcaneal tendon, bronchial epithelial cell
STX19	176	tissue_specific	marker	mucosa of transverse colon, esophagus squamous epithelium, rectum
NSUN3	231	ubiquitous	marker	sperm, male germ cell, calcaneal tendon
DHFR2	249	ubiquitous	marker	buccal mucosa cell, pancreatic ductal cell, kidney epithelium
PROS1	276	ubiquitous	marker	choroid plexus epithelium, bronchial epithelial cell, synovial joint

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHFR2	3,135
ARL13B	2,558
NSUN3	1,872
PROS1	1,129
STX19	928

Structural data

PDB: 1 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PROS1	P07225	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DHFR2	Q86XF0	96.06
NSUN3	Q9H649	90.97
STX19	Q8N4C7	78.14
ARL13B	Q3SXY8	72.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 5 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ARL13B-mediated ciliary trafficking of INPP5E	1	1268.9×	0.008	ARL13B
Defective cleavage of FV variant at a.a.534	1	1268.9×	0.008	PROS1
Defective cleavage of FV variant at R334	1	1268.9×	0.008	PROS1
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	423.0×	0.013	PROS1
Gamma-carboxylation of protein precursors	1	380.7×	0.013	PROS1
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	380.7×	0.013	PROS1
Metabolism of folate and pterines	1	211.5×	0.017	DHFR2
Amplification and propagation of coagulation cascade	1	211.5×	0.017	PROS1
Chaperone Mediated Autophagy	1	165.5×	0.018	ARL13B
Initiation of coagulation cascade	1	158.6×	0.018	PROS1
Late endosomal microautophagy	1	108.8×	0.022	ARL13B
Selective autophagy	1	92.8×	0.022	ARL13B
Dengue Virus Attachment and Entry	1	86.5×	0.022	PROS1
Cargo trafficking to the periciliary membrane	1	82.8×	0.022	ARL13B
Aggrephagy	1	82.8×	0.022	ARL13B
Regulation of clotting cascade	1	77.7×	0.022	PROS1
Regulation of Complement cascade	1	77.7×	0.022	PROS1
RHOJ GTPase cycle	1	66.8×	0.024	ARL13B
RHOQ GTPase cycle	1	60.4×	0.025	ARL13B
Autophagy	1	49.4×	0.029	ARL13B
Macroautophagy	1	38.5×	0.036	ARL13B
Cilium Assembly	1	36.2×	0.036	ARL13B
Cell surface interactions at the vascular wall	1	31.7×	0.039	PROS1
Platelet degranulation	1	29.3×	0.041	PROS1
Organelle biogenesis and maintenance	1	22.0×	0.052	ARL13B
RHO GTPase cycle	1	20.0×	0.055	ARL13B
Signaling by Rho GTPases	1	11.4×	0.090	ARL13B
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.090	ARL13B
Signal Transduction	1	3.4×	0.267	ARL13B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tRNA wobble base cytosine methylation	1	3370.4×	0.004	NSUN3
interneuron migration from the subpallium to the cortex	1	3370.4×	0.004	ARL13B
thymidine biosynthetic process	1	1123.5×	0.005	DHFR2
dihydrofolate metabolic process	1	1123.5×	0.005	DHFR2
formation of radial glial scaffolds	1	842.6×	0.005	ARL13B
receptor localization to non-motile cilium	1	674.1×	0.005	ARL13B
neural tube patterning	1	561.7×	0.005	ARL13B
tetrahydrofolate biosynthetic process	1	561.7×	0.005	DHFR2
tetrahydrofolate metabolic process	1	481.5×	0.005	DHFR2
regulation of mitochondrial translation	1	481.5×	0.005	NSUN3
synaptic vesicle fusion to presynaptic active zone membrane	1	337.0×	0.007	STX19
rRNA methylation	1	280.9×	0.008	NSUN3
left/right axis specification	1	240.7×	0.008	ARL13B
one-carbon metabolic process	1	224.7×	0.008	DHFR2
folic acid metabolic process	1	224.7×	0.008	DHFR2
fibrinolysis	1	168.5×	0.010	PROS1
obsolete vesicle docking	1	153.2×	0.010	STX19
dorsal/ventral pattern formation	1	84.3×	0.017	ARL13B
non-motile cilium assembly	1	58.1×	0.023	ARL13B
heart looping	1	53.5×	0.024	ARL13B
smoothened signaling pathway	1	36.2×	0.034	ARL13B
blood coagulation	1	34.8×	0.034	PROS1
exocytosis	1	30.4×	0.037	STX19
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	15.7×	0.067	PROS1
cilium assembly	1	14.7×	0.069	ARL13B
intracellular protein transport	1	13.0×	0.075	STX19

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARL13B	0	0
STX19	0	0
NSUN3	0	0
DHFR2	0	0
PROS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NSUN3	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSUN3	2.1.1.203	tRNA (cytosine34-C5)-methyltransferase
DHFR2	1.5.1.3	dihydrofolate reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	NSUN3, DHFR2
E	Difficult family or no structure, no drug	3	ARL13B, STX19, PROS1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ARL13B	0	—
STX19	0	—
NSUN3	5	—
DHFR2	0	—
PROS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.