Joubert syndrome 9

Summary

Joubert syndrome 9 (MONDO:0012849) is a disease caused by CC2D2A (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: CC2D2A (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 445

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 9
Mondo ID	MONDO:0012849
MeSH	C567364
OMIM	612285
DOID	DOID:0111004
NCIT	C181002
UMLS	C2676788
MedGen	382940
GARD	0015549
Is cancer (heuristic)	no

Also known as: CC2D2A Joubert syndrome · JBTS9 · Joubert syndrome 9 · Joubert syndrome caused by mutation in CC2D2A · Joubert syndrome type 9

Data availability: 445 ClinVar variants · 3 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome with oculorenal defect › Joubert syndrome 9

Related subtypes (4): Joubert syndrome 2, Joubert syndrome 5, Joubert syndrome 14, Joubert syndrome 16

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

445 retrieved; paginated sample, class counts are floors:

196 uncertain significance, 108 conflicting classifications of pathogenicity, 47 pathogenic/likely pathogenic, 39 likely pathogenic, 31 pathogenic, 18 benign, 4 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071905	NM_001378615.1(CC2D2A):c.4256del (p.Gly1419fs)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1074596	NM_001378615.1(CC2D2A):c.1538G>A (p.Trp513Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
126242	NM_001378615.1(CC2D2A):c.394C>T (p.Arg132Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285429	NM_001378615.1(CC2D2A):c.4786G>A (p.Ala1596Thr)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297595	NM_001378615.1(CC2D2A):c.712G>T (p.Glu238Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1317486	NM_001378615.1(CC2D2A):c.4333C>T (p.Arg1445Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322034	NM_001378615.1(CC2D2A):c.3763C>T (p.Arg1255Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395827	NM_001378615.1(CC2D2A):c.3688C>T (p.Arg1230Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1427276	NM_001378615.1(CC2D2A):c.4522del (p.Ile1508fs)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456425	NM_001378615.1(CC2D2A):c.121C>T (p.Gln41Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
166801	NM_001378615.1(CC2D2A):c.1017+1G>A	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805718	NM_001378615.1(CC2D2A):c.2710G>T (p.Glu904Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1904397	NM_001378615.1(CC2D2A):c.3535G>T (p.Glu1179Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191188	NM_001378615.1(CC2D2A):c.4437+1G>A	CC2D2A	Pathogenic	criteria provided, single submitter
1930499	NM_001378615.1(CC2D2A):c.4229G>A (p.Trp1410Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
210609	NM_001378615.1(CC2D2A):c.2683C>T (p.Gln895Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210612	NM_001378615.1(CC2D2A):c.4465_4468del (p.Asp1489fs)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217594	NM_001378615.1(CC2D2A):c.4289T>C (p.Val1430Ala)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217596	NM_001378615.1(CC2D2A):c.3892_3893del (p.Val1298fs)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
217597	NM_001378615.1(CC2D2A):c.3850C>T (p.Arg1284Cys)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217599	NM_001378615.1(CC2D2A):c.3744_3747dup (p.Pro1250fs)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
217600	NM_001378615.1(CC2D2A):c.3772-1G>T	CC2D2A	Pathogenic	criteria provided, single submitter
217601	NM_001378615.1(CC2D2A):c.3134T>C (p.Val1045Ala)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217602	NM_001378615.1(CC2D2A):c.3055C>T (p.Arg1019Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217603	NM_001378615.1(CC2D2A):c.4741A>G (p.Thr1581Ala)	CC2D2A	Pathogenic	criteria provided, single submitter
217604	NM_001378615.1(CC2D2A):c.2999A>T (p.Glu1000Val)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217605	NM_001378615.1(CC2D2A):c.2624C>A (p.Ser875Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
217607	NM_001378615.1(CC2D2A):c.4667A>T (p.Asp1556Val)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217609	NM_001378615.1(CC2D2A):c.4226T>C (p.Ile1409Thr)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217610	NM_001378615.1(CC2D2A):c.1676T>C (p.Leu559Pro)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 8 · 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
CC2D2A	Definitive	Autosomal recessive	Joubert syndrome 9	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CC2D2A	Orphanet:1454	Joubert syndrome with hepatic defect
CC2D2A	Orphanet:2318	Joubert syndrome with oculorenal defect
CC2D2A	Orphanet:564	Meckel syndrome
CC2D2A	Orphanet:791	Retinitis pigmentosa
RPE65	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
RPE65	Orphanet:65	Leber congenital amaurosis
RPE65	Orphanet:791	Retinitis pigmentosa
SMAD6	Orphanet:402075	Familial bicuspid aortic valve

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CC2D2A	HGNC:29253	ENSG00000048342	Q9P2K1	Coiled-coil and C2 domain-containing protein 2A	gencc,clinvar
RPE65	HGNC:10294	ENSG00000116745	Q16518	Retinoid isomerohydrolase	clinvar
SMAD6	HGNC:6772	ENSG00000137834	O43541	SMAD family member 6	clinvar
OXTR	HGNC:8529	ENSG00000180914	P30559	Oxytocin receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CC2D2A	Coiled-coil and C2 domain-containing protein 2A	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
RPE65	Retinoid isomerohydrolase	Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.
SMAD6	SMAD family member 6	Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators.
OXTR	Oxytocin receptor	Receptor for oxytocin.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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
Protease	1	9.2×	0.314
GPCR	1	6.0×	0.314
Enzyme (other)	1	3.0×	0.392
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CC2D2A	Protease	yes		C2_dom, CC2D2AN-C2, C2_domain_sf
RPE65	Enzyme (other)	yes	3.1.1.64	Carotenoid_Oase
SMAD6	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
OXTR	GPCR	yes		GPCR_Rhodpsn, Vasoprsn_rcpt, Oxytocn_rcpt

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	2
bronchus	1
right uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	1
retina	1
metanephric glomerulus	1
renal glomerulus	1
right lung	1
decidua	1
epithelium of mammary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CC2D2A	247	ubiquitous	marker	right uterine tube, bronchial epithelial cell, bronchus
RPE65	92	tissue_specific	marker	pigmented layer of retina, retina, male germ line stem cell (sensu Vertebrata) in testis
SMAD6	277	ubiquitous	marker	right lung, renal glomerulus, metanephric glomerulus
OXTR	204	broad	yes	decidua, bronchial epithelial cell, epithelium of mammary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD6	2,006
OXTR	1,420
RPE65	1,414
CC2D2A	899

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OXTR	P30559	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RPE65	Q16518	95.34
SMAD6	O43541	72.34
CC2D2A	Q9P2K1	69.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vasopressin-like receptors	1	475.8×	0.034	OXTR
RUNX2 regulates bone development	1	203.9×	0.039	SMAD6
The canonical retinoid cycle in rods (twilight vision)	1	129.8×	0.041	RPE65
Signaling by BMP	1	89.2×	0.042	SMAD6
Visual phototransduction	1	64.9×	0.042	RPE65
Transcriptional regulation by RUNX2	1	63.4×	0.042	SMAD6
Signaling by TGFB family members	1	28.8×	0.064	SMAD6
Anchoring of the basal body to the plasma membrane	1	28.3×	0.064	CC2D2A
Cilium Assembly	1	27.2×	0.064	CC2D2A
Sensory Perception	1	23.8×	0.066	RPE65
Organelle biogenesis and maintenance	1	16.5×	0.086	CC2D2A
G alpha (q) signalling events	1	14.3×	0.091	OXTR
RNA Polymerase II Transcription	1	5.6×	0.204	SMAD6
Gene expression (Transcription)	1	4.5×	0.235	SMAD6
Generic Transcription Pathway	1	3.8×	0.256	SMAD6
Signal Transduction	1	2.5×	0.339	SMAD6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
zeaxanthin biosynthetic process	1	4213.0×	0.014	RPE65
zygotic specification of dorsal/ventral axis	1	1404.3×	0.014	SMAD6
response to laminar fluid shear stress	1	1053.2×	0.014	SMAD6
regulation of systemic arterial blood pressure by vasopressin	1	842.6×	0.014	OXTR
maternal process involved in parturition	1	842.6×	0.014	OXTR
vitamin A metabolic process	1	601.9×	0.014	RPE65
protein localization to ciliary transition zone	1	601.9×	0.014	CC2D2A
mitral valve morphogenesis	1	421.3×	0.017	SMAD6
negative regulation of activin receptor signaling pathway	1	351.1×	0.017	SMAD6
retina homeostasis	1	280.9×	0.017	RPE65
positive regulation of blood pressure	1	263.3×	0.017	OXTR
pulmonary valve morphogenesis	1	234.1×	0.017	SMAD6
neural retina development	1	234.1×	0.017	RPE65
retinal metabolic process	1	234.1×	0.017	RPE65
embryonic brain development	1	200.6×	0.017	CC2D2A
cell-substrate adhesion	1	191.5×	0.017	SMAD6
SMAD protein signal transduction	1	183.2×	0.017	SMAD6
outflow tract septum morphogenesis	1	162.0×	0.017	SMAD6
detection of light stimulus involved in visual perception	1	162.0×	0.017	RPE65
negative regulation of ossification	1	156.0×	0.017	SMAD6
coronary vasculature development	1	156.0×	0.017	SMAD6
positive regulation of vasoconstriction	1	150.5×	0.017	OXTR
negative regulation of SMAD protein signal transduction	1	150.5×	0.017	SMAD6
motile cilium assembly	1	145.3×	0.017	CC2D2A
aorta development	1	140.4×	0.017	SMAD6
axoneme assembly	1	135.9×	0.017	CC2D2A
retinoid metabolic process	1	123.9×	0.018	RPE65
ventricular septum development	1	123.9×	0.018	SMAD6
ureteric bud development	1	113.9×	0.018	SMAD6
aortic valve morphogenesis	1	108.0×	0.019	SMAD6

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
OXTR	DESMOPRESSIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OXTR	15	4
CC2D2A	0	0
RPE65	0	0
SMAD6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DESMOPRESSIN	4	OXTR
CARBETOCIN	4	OXTR
VASOPRESSIN	4	OXTR
ATOSIBAN	4	OXTR
OXYTOCIN	4	OXTR
MOZAVAPTAN	4	OXTR
NOLASIBAN	3	OXTR
SEMAXANIB	3	OXTR
RETOSIBAN	3	OXTR
LIXIVAPTAN	3	OXTR
SELEPRESSIN	2	OXTR
ORNIPRESSIN	2	OXTR
EPELSIBAN	2	OXTR
PECAVAPTAN	2	OXTR
NELIVAPTAN	2	OXTR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
OXTR	249	Binding:149, Functional:99, Unclassified:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPE65	3.1.1.64, 5.3.3.22	retinoid isomerohydrolase, lutein isomerase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
OXTR	249

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

15 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.

Compound	Max phase	Cohort target (bioactivity)
DESMOPRESSIN	4	OXTR
CARBETOCIN	4	OXTR
VASOPRESSIN	4	OXTR
ATOSIBAN	4	OXTR
OXYTOCIN	4	OXTR
MOZAVAPTAN	4	OXTR
NOLASIBAN	3	OXTR
SEMAXANIB	3	OXTR
RETOSIBAN	3	OXTR
LIXIVAPTAN	3	OXTR
SELEPRESSIN	2	OXTR
ORNIPRESSIN	2	OXTR
EPELSIBAN	2	OXTR
PECAVAPTAN	2	OXTR
NELIVAPTAN	2	OXTR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	OXTR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	CC2D2A, RPE65
E	Difficult family or no structure, no drug	1	SMAD6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CC2D2A	0	—
RPE65	0	—
SMAD6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.