Joubert syndrome 21

Summary

Joubert syndrome 21 (MONDO:0014288) is a disease caused by CSPP1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: CSPP1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,120

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 21
Mondo ID	MONDO:0014288
OMIM	615636
DOID	DOID:0110990
UMLS	C3810212
MedGen	816542
GARD	0015997
Is cancer (heuristic)	no

Also known as: CSPP1 Joubert syndrome · JBTS21 · Joubert syndrome 21 · Joubert syndrome caused by mutation in CSPP1 · Joubert syndrome type 21

Data availability: 1,120 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive congenital cerebellar ataxia › Joubert syndrome and related disorders › Joubert syndrome with Jeune asphyxiating thoracic dystrophy › Joubert syndrome 21

Related subtypes (1): short-rib thoracic dysplasia 14 with polydactyly

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

600 retrieved; paginated sample, class counts are floors:

338 uncertain significance, 192 likely benign, 38 pathogenic, 11 likely pathogenic, 11 benign, 7 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100669	NM_001382391.1(CSPP1):c.3227dup (p.Tyr1076Ter)	ARFGEF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069030	NM_001382391.1(CSPP1):c.2980C>T (p.Arg994Ter)	ARFGEF1	Pathogenic	criteria provided, single submitter
1072911	NM_001382391.1(CSPP1):c.3406_3407insTATA (p.Arg1136delinsIleTer)	ARFGEF1	Pathogenic	criteria provided, single submitter
1322167	NM_001382391.1(CSPP1):c.3142C>T (p.Arg1048Ter)	ARFGEF1	Pathogenic	criteria provided, single submitter
1445486	NM_001382391.1(CSPP1):c.3405_3406del (p.Arg1136fs)	ARFGEF1	Pathogenic	criteria provided, single submitter
1455984	NM_001382391.1(CSPP1):c.3368_3371del (p.Leu1122_Ser1123insTer)	ARFGEF1	Pathogenic	criteria provided, single submitter
1933382	NM_001382391.1(CSPP1):c.3266del (p.Pro1089fs)	ARFGEF1	Pathogenic	criteria provided, single submitter
100666	NM_001382391.1(CSPP1):c.2335C>T (p.Arg779Ter)	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
100667	NM_001382391.1(CSPP1):c.2259_2260del (p.Glu755fs)	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
100668	NM_001382391.1(CSPP1):c.2295del (p.Glu766fs)	CSPP1	Pathogenic	criteria provided, single submitter
100670	NM_001382391.1(CSPP1):c.2968+1G>A	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
100671	NM_001382391.1(CSPP1):c.2542_2543del (p.Met848fs)	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
100672	NM_001382391.1(CSPP1):c.631C>T (p.Arg211Ter)	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
100673	NM_001382391.1(CSPP1):c.255_256del (p.His85fs)	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
100674	NM_001382391.1(CSPP1):c.2259_2262del (p.Glu755fs)	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
100675	NM_001382391.1(CSPP1):c.625C>T (p.Gln209Ter)	CSPP1	Pathogenic	no assertion criteria provided
100676	NM_001382391.1(CSPP1):c.2788C>T (p.Arg930Ter)	CSPP1	Pathogenic	no assertion criteria provided
1030873	NM_001382391.1(CSPP1):c.132dup (p.Lys45Ter)	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1031405	NM_001382391.1(CSPP1):c.2521_2524del (p.Ile841fs)	CSPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070338	NM_001382391.1(CSPP1):c.1544_1547del (p.Asn515fs)	CSPP1	Pathogenic	criteria provided, single submitter
1184140	NM_001382391.1(CSPP1):c.1698-1G>C	CSPP1	Pathogenic	criteria provided, single submitter
1322166	NM_001382391.1(CSPP1):c.1822C>T (p.Gln608Ter)	CSPP1	Pathogenic	criteria provided, single submitter
1322168	NM_001382391.1(CSPP1):c.2538+1G>T	CSPP1	Pathogenic	criteria provided, single submitter
1350495	NM_001382391.1(CSPP1):c.-69C>T	CSPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1359163	NM_001382391.1(CSPP1):c.1505del (p.Pro502fs)	CSPP1	Pathogenic	criteria provided, single submitter
1451541	NM_001382391.1(CSPP1):c.1787_1790del (p.Lys596fs)	CSPP1	Pathogenic	criteria provided, single submitter
1453060	NM_001382391.1(CSPP1):c.2285_2286del (p.Leu762fs)	CSPP1	Pathogenic	criteria provided, single submitter
1453404	NM_001382391.1(CSPP1):c.419_422del (p.Asn140fs)	CSPP1	Pathogenic	criteria provided, single submitter
1453492	NM_001382391.1(CSPP1):c.263_267del (p.Lys88fs)	CSPP1	Pathogenic	criteria provided, single submitter
1458414	NC_000008.10:g.(?67998222)(67998365_?)del	CSPP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
CSPP1	Definitive	Autosomal recessive	Joubert syndrome 21	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CSPP1	Orphanet:397715	Joubert syndrome with Jeune asphyxiating thoracic dystrophy
CSPP1	Orphanet:475	Isolated Joubert syndrome
CSPP1	Orphanet:564	Meckel syndrome

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
CSPP1	HGNC:26193	ENSG00000104218	Q1MSJ5	Centrosome and spindle pole-associated protein 1	gencc,clinvar
ARFGEF1	HGNC:15772	ENSG00000066777	Q9Y6D6	Brefeldin A-inhibited guanine nucleotide-exchange protein 1	clinvar
COPS5	HGNC:2240	ENSG00000121022	Q92905	COP9 signalosome complex subunit 5	clinvar
PPP1R42	HGNC:33732	ENSG00000178125	Q7Z4L9	Protein phosphatase 1 regulatory subunit 42	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CSPP1	Centrosome and spindle pole-associated protein 1	May play a role in cell-cycle-dependent microtubule organization.
ARFGEF1	Brefeldin A-inhibited guanine nucleotide-exchange protein 1	Promotes guanine-nucleotide exchange on ARF1 and ARF3.
COPS5	COP9 signalosome complex subunit 5	Probable protease subunit of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes.
PPP1R42	Protein phosphatase 1 regulatory subunit 42	Regulates phosphatase activity of protein phosphatase 1 (PP1) complexes in the testis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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×	0.210
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CSPP1	Other/Unknown	no		CSPP1, CSPP1_C
ARFGEF1	Other/Unknown	no		Sec7_dom, ARM-like, Mon2/Sec7/BIG1-like_HDS
COPS5	Protease	yes		JAMM/MPN+_dom, MPN, CSN5_C
PPP1R42	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_4, LRR_dom_sf

Expression context

Cohort genes with no expression data: 0.

4 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
right uterine tube	2
sperm	2
bronchial epithelial cell	1
epithelium of nasopharynx	1
primordial germ cell in gonad	1
secondary oocyte	1
heart right ventricle	1
male germ cell	1
left testis	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CSPP1	275	ubiquitous	marker	bronchial epithelial cell, sperm, right uterine tube
ARFGEF1	298	ubiquitous	marker	primordial germ cell in gonad, secondary oocyte, epithelium of nasopharynx
COPS5	295	ubiquitous	marker	sperm, heart right ventricle, male germ cell
PPP1R42	122	broad	marker	right uterine tube, olfactory segment of nasal mucosa, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COPS5	6,801
ARFGEF1	2,450
CSPP1	2,300
PPP1R42	2,000

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COPS5	Q92905	31
ARFGEF1	Q9Y6D6	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PPP1R42	Q7Z4L9	86.02
CSPP1	Q1MSJ5	57.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DNA Damage Recognition in GG-NER	1	285.5×	0.008	COPS5
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	237.9×	0.008	COPS5
Formation of TC-NER Pre-Incision Complex	1	211.5×	0.008	COPS5
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.012	COPS5
Neddylation	1	47.4×	0.021	COPS5

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endomembrane system organization	1	2808.7×	0.006	ARFGEF1
regulation of IRE1-mediated unfolded protein response	1	1872.4×	0.006	COPS5
exosomal secretion	1	1404.3×	0.006	COPS5
protein deneddylation	1	432.1×	0.009	COPS5
negative regulation of GTPase activity	1	351.1×	0.009	ARFGEF1
negative regulation of actin filament polymerization	1	312.1×	0.009	ARFGEF1
regulation of establishment of cell polarity	1	312.1×	0.009	ARFGEF1
regulation of protein neddylation	1	312.1×	0.009	COPS5
regulation of ARF protein signal transduction	1	295.6×	0.009	ARFGEF1
regulation of JNK cascade	1	295.6×	0.009	COPS5
protein neddylation	1	234.1×	0.010	COPS5
obsolete positive regulation of DNA-binding transcription factor activity	1	200.6×	0.011	COPS5
positive regulation of wound healing	1	175.5×	0.012	ARFGEF1
post-translational protein modification	1	140.4×	0.013	COPS5
positive regulation of cytokinesis	1	133.8×	0.013	CSPP1
glycoprotein biosynthetic process	1	112.3×	0.014	ARFGEF1
positive regulation of cell division	1	112.3×	0.014	CSPP1
exocytosis	1	50.6×	0.029	ARFGEF1
Golgi organization	1	44.6×	0.032	ARFGEF1
neuron projection development	1	40.7×	0.033	ARFGEF1
translation	1	34.2×	0.037	COPS5
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	26.1×	0.046	ARFGEF1
regulation of cell cycle	1	24.9×	0.047	COPS5
protein transport	1	14.6×	0.075	ARFGEF1
negative regulation of apoptotic process	1	11.6×	0.088	COPS5
proteolysis	1	11.4×	0.088	COPS5
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	COPS5

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
COPS5	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COPS5	1	4
CSPP1	0	0
ARFGEF1	0	0
PPP1R42	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	COPS5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
COPS5	48	Binding:48
CSPP1	1	Binding:1
ARFGEF1	1	Binding:1

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

1 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)
BERBERINE	4	COPS5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	COPS5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	CSPP1, ARFGEF1, PPP1R42

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)
CSPP1	1	—
ARFGEF1	1	—
PPP1R42	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.