Joubert syndrome 2

Summary

Joubert syndrome 2 (MONDO:0011963) is a disease caused by TMEM216 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TMEM216 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 131

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 2
Mondo ID	MONDO:0011963
MeSH	C536294
OMIM	608091
DOID	DOID:0110988
UMLS	C1842577
MedGen	334114
GARD	0010167
Is cancer (heuristic)	no

Also known as: cerebellooculorenal syndrome 2 · CORS2 · JBTS2 · Joubert syndrome 2 · Joubert syndrome caused by mutation in TMEM216 · Joubert syndrome type 2 · TMEM216 Joubert syndrome

Data availability: 131 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome with oculorenal defect › Joubert syndrome 2

Related subtypes (4): Joubert syndrome 5, Joubert syndrome 9, 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

131 retrieved; paginated sample, class counts are floors:

62 uncertain significance, 24 likely pathogenic, 18 conflicting classifications of pathogenicity, 8 likely benign, 5 pathogenic/likely pathogenic, 5 benign, 5 benign/likely benign, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073194	NM_001173990.3(TMEM216):c.87G>A (p.Trp29Ter)	TMEM216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1176283	NM_001173990.3(TMEM216):c.191del (p.Leu64fs)	TMEM216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197	NM_001173990.3(TMEM216):c.218G>T (p.Arg73Leu)	TMEM216	Pathogenic	criteria provided, multiple submitters, no conflicts
198	NM_001173990.3(TMEM216):c.218G>A (p.Arg73His)	TMEM216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217704	NM_001173990.3(TMEM216):c.398T>G (p.Leu133Ter)	TMEM216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679223	NM_001173990.3(TMEM216):c.222_229+3delinsTTTTTTTGTT	TMEM216	Pathogenic	criteria provided, single submitter
371710	NM_001173990.3(TMEM216):c.228dup (p.Gly77fs)	TMEM216	Pathogenic	criteria provided, single submitter
56384	NM_001173990.3(TMEM216):c.253C>T (p.Arg85Ter)	TMEM216	Pathogenic	criteria provided, multiple submitters, no conflicts
591162	NM_001173990.3(TMEM216):c.67del (p.Leu23fs)	TMEM216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066361	NM_001173990.3(TMEM216):c.137-2A>G	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1494212	NM_001173990.3(TMEM216):c.229+1G>A	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679220	NM_001173990.3(TMEM216):c.86G>A (p.Trp29Ter)	TMEM216	Likely pathogenic	criteria provided, single submitter
2679221	NM_001173990.3(TMEM216):c.302_303insCATT (p.Met101fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
2679222	NM_001173990.3(TMEM216):c.229+1G>C	TMEM216	Likely pathogenic	criteria provided, single submitter
2679224	NM_001173990.3(TMEM216):c.34+1G>A	TMEM216	Likely pathogenic	criteria provided, single submitter
2679225	NM_001173990.3(TMEM216):c.222_224delinsA (p.Phe76fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
2679226	NM_001173990.3(TMEM216):c.112G>T (p.Glu38Ter)	TMEM216	Likely pathogenic	criteria provided, single submitter
3240614	NM_001173990.3(TMEM216):c.193_194delinsA (p.Leu65fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
3599817	NM_001173990.3(TMEM216):c.230-1G>C	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599818	NM_001173990.3(TMEM216):c.246_247del (p.Cys83fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
371740	NM_001173990.3(TMEM216):c.34+2T>C	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
371759	NM_001173990.3(TMEM216):c.222del (p.Phe76fs)	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
371763	NM_001173990.3(TMEM216):c.228del (p.Phe76fs)	TMEM216	Likely pathogenic	no assertion criteria provided
371778	NM_001173990.3(TMEM216):c.35-2A>G	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
376902	NM_001173990.3(TMEM216):c.35-13_36del	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3892663	NM_001173990.3(TMEM216):c.395_398del (p.Leu132fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
4814685	NM_001173990.3(TMEM216):c.40_41insT (p.Arg14fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
4814686	NM_001173990.3(TMEM216):c.40del (p.Arg14fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
551831	NM_001173990.3(TMEM216):c.164_168del (p.Asn55fs)	TMEM216	Likely pathogenic	no assertion criteria provided
554706	NM_001173990.3(TMEM216):c.336C>A (p.Tyr112Ter)	TMEM216	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
TMEM216	Strong	Autosomal recessive	Joubert syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM216	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM216	Orphanet:2754	Orofaciodigital syndrome type 6
TMEM216	Orphanet:564	Meckel syndrome
TMEM216	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM216	HGNC:25018	ENSG00000187049	Q9P0N5	Transmembrane protein 216	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM216	Transmembrane protein 216	Essential for primary ciliogenesis and embryonic development, facilitating the activation of Hedgehog (Hh) signaling pathway.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM216	Other/Unknown	no		Uncharacterised_TM-17

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
pituitary gland	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM216	239	ubiquitous	marker	primordial germ cell in gonad, adenohypophysis, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM216	946

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM216	Q9P0N5	89.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
Anchoring of the basal body to the plasma membrane	1	113.1×	0.009	TMEM216

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
photoreceptor cell morphogenesis	1	2808.7×	0.002	TMEM216
positive regulation of cilium assembly	1	766.0×	0.004	TMEM216
positive regulation of smoothened signaling pathway	1	421.3×	0.004	TMEM216
photoreceptor cell maintenance	1	358.6×	0.004	TMEM216
non-motile cilium assembly	1	290.6×	0.004	TMEM216
cilium assembly	1	73.6×	0.014	TMEM216

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMEM216	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	1	TMEM216

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM216	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.