Joubert syndrome 7

Summary

Joubert syndrome 7 (MONDO:0012694) is a disease caused by RPGRIP1L (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: RPGRIP1L (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 489

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 7
Mondo ID	MONDO:0012694
MeSH	C566916
OMIM	611560
DOID	DOID:0111002
NCIT	C159653
UMLS	C1969053
MedGen	369401
GARD	0015519
Is cancer (heuristic)	no

Also known as: JBTS7 · Joubert syndrome 7 · Joubert syndrome caused by mutation in RPGRIP1L · Joubert syndrome type 7 · RPGRIP1L Joubert syndrome

Data availability: 489 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome › Joubert syndrome 7

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 9, Joubert syndrome 8, 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

489 retrieved; paginated sample, class counts are floors:

263 uncertain significance, 68 conflicting classifications of pathogenicity, 53 pathogenic/likely pathogenic, 41 likely pathogenic, 26 likely benign, 15 pathogenic, 12 benign, 11 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065930	NM_015272.5(RPGRIP1L):c.530-1G>C	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068	NM_015272.5(RPGRIP1L):c.697A>T (p.Lys233Ter)	RPGRIP1L	Pathogenic	criteria provided, multiple submitters, no conflicts
1069	NM_015272.5(RPGRIP1L):c.1843A>C (p.Thr615Pro)	RPGRIP1L	Pathogenic	criteria provided, multiple submitters, no conflicts
1069014	NM_015272.5(RPGRIP1L):c.2432del (p.Pro811fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069456	NM_015272.5(RPGRIP1L):c.3607del (p.Tyr1203fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070	NM_015272.5(RPGRIP1L):c.757C>T (p.Gln253Ter)	RPGRIP1L	Pathogenic	criteria provided, multiple submitters, no conflicts
1071109	NM_015272.5(RPGRIP1L):c.170T>A (p.Leu57Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071183	NM_015272.5(RPGRIP1L):c.2149_2152del (p.Ile717fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071605	NM_015272.5(RPGRIP1L):c.1645G>T (p.Glu549Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071757	NM_015272.5(RPGRIP1L):c.1372G>T (p.Glu458Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072021	NM_015272.5(RPGRIP1L):c.772C>T (p.Gln258Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072712	NM_015272.5(RPGRIP1L):c.2093T>G (p.Leu698Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074	NM_015272.5(RPGRIP1L):c.2614C>T (p.Gln872Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076	NM_015272.5(RPGRIP1L):c.2050C>T (p.Gln684Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1077	NM_015272.5(RPGRIP1L):c.2269del (p.Thr757fs)	RPGRIP1L	Pathogenic	no assertion criteria provided
1079	NM_015272.5(RPGRIP1L):c.2413C>T (p.Arg805Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1080	NM_015272.5(RPGRIP1L):c.1975T>C (p.Ser659Pro)	RPGRIP1L	Pathogenic	criteria provided, single submitter
1185043	NM_015272.5(RPGRIP1L):c.1351-11A>G	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1358982	NM_015272.5(RPGRIP1L):c.1171C>T (p.Gln391Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1442552	NM_015272.5(RPGRIP1L):c.1978C>T (p.Gln660Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1446214	NM_015272.5(RPGRIP1L):c.2493del (p.Ser832fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451391	NM_015272.5(RPGRIP1L):c.599T>G (p.Leu200Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451910	NM_015272.5(RPGRIP1L):c.1608_1614del (p.Met537fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453353	NM_015272.5(RPGRIP1L):c.71dup (p.Met24fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454714	NM_015272.5(RPGRIP1L):c.2591_2592del (p.Tyr864fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456256	NM_015272.5(RPGRIP1L):c.1959del (p.Glu654fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457129	NM_015272.5(RPGRIP1L):c.2451C>A (p.Tyr817Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459489	NM_015272.5(RPGRIP1L):c.2239C>T (p.Arg747Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188192	NM_015272.5(RPGRIP1L):c.1709dup (p.Asp571fs)	RPGRIP1L	Pathogenic	criteria provided, multiple submitters, no conflicts
1896983	NM_015272.5(RPGRIP1L):c.3682C>T (p.Gln1228Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 7 · 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
RPGRIP1L	Strong	Autosomal recessive	Joubert syndrome 7	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPGRIP1L	Orphanet:1454	Joubert syndrome with hepatic defect
RPGRIP1L	Orphanet:220497	Joubert syndrome with renal defect
RPGRIP1L	Orphanet:564	Meckel syndrome
RPGRIP1	Orphanet:1872	Cone rod dystrophy
RPGRIP1	Orphanet:564	Meckel syndrome
RPGRIP1	Orphanet:65	Leber congenital amaurosis
PKD2	Orphanet:730	Autosomal dominant polycystic kidney disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPGRIP1L	HGNC:29168	ENSG00000103494	Q68CZ1	Protein fantom	gencc,clinvar
RPGRIP1	HGNC:13436	ENSG00000092200	Q96KN7	X-linked retinitis pigmentosa GTPase regulator-interacting protein 1	clinvar
PKD2	HGNC:9009	ENSG00000118762	Q13563	Polycystin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPGRIP1L	Protein fantom	Negatively regulates signaling through the G-protein coupled thromboxane A2 receptor (TBXA2R).
RPGRIP1	X-linked retinitis pigmentosa GTPase regulator-interacting protein 1	May function as scaffolding protein.
PKD2	Polycystin-2	Forms a nonselective cation channel.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPGRIP1L	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
RPGRIP1	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
PKD2	Other/Unknown	no		EF_hand_dom, PKD_2, EF-hand-dom_pair

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
left testis	1
right testis	1
sperm	1
blood vessel layer	1
calcaneal tendon	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPGRIP1L	207	ubiquitous	marker	bronchial epithelial cell, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
RPGRIP1	168	tissue_specific	marker	left testis, sperm, right testis
PKD2	288	ubiquitous	marker	blood vessel layer, calcaneal tendon, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPGRIP1L	2,027
PKD2	1,644
RPGRIP1	1,422

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PKD2	Q13563	31
RPGRIP1L	Q68CZ1	1
RPGRIP1	Q96KN7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
VxPx cargo-targeting to cilium	1	259.6×	0.012	PKD2
Hedgehog ‘off’ state	1	89.2×	0.017	RPGRIP1L
Anchoring of the basal body to the plasma membrane	1	56.5×	0.018	RPGRIP1L

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
retinal rod cell development	2	1123.5×	7e-05	RPGRIP1L, RPGRIP1
non-motile cilium assembly	2	193.7×	0.001	RPGRIP1L, RPGRIP1
determination of left/right symmetry	2	170.2×	0.001	RPGRIP1L, PKD2
liver development	2	147.8×	0.001	RPGRIP1L, PKD2
metanephric cortex development	1	5617.3×	0.002	PKD2
metanephric cortical collecting duct development	1	5617.3×	0.002	PKD2
metanephric distal tubule development	1	5617.3×	0.002	PKD2
renal artery morphogenesis	1	2808.7×	0.003	PKD2
mesonephric tubule development	1	2808.7×	0.003	PKD2
metanephric smooth muscle tissue development	1	2808.7×	0.003	PKD2
detection of nodal flow	1	1872.4×	0.003	PKD2
cellular response to hydrostatic pressure	1	1872.4×	0.003	PKD2
metanephric part of ureteric bud development	1	1404.3×	0.003	PKD2
renal tubule morphogenesis	1	1404.3×	0.003	PKD2
metanephric ascending thin limb development	1	1404.3×	0.003	PKD2
metanephric S-shaped body morphogenesis	1	1404.3×	0.003	PKD2
mesonephric duct development	1	1123.5×	0.004	PKD2
neural tube patterning	1	936.2×	0.004	RPGRIP1L
determination of liver left/right asymmetry	1	936.2×	0.004	PKD2
nose development	1	802.5×	0.004	RPGRIP1L
metanephric mesenchyme development	1	802.5×	0.004	PKD2
positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway	1	802.5×	0.004	PKD2
regulation of calcium ion import	1	702.2×	0.005	PKD2
pericardium development	1	624.1×	0.005	RPGRIP1L
placenta blood vessel development	1	468.1×	0.006	PKD2
lateral ventricle development	1	432.1×	0.006	RPGRIP1L
cellular response to fluid shear stress	1	432.1×	0.006	PKD2
negative regulation of G protein-coupled receptor signaling pathway	1	401.2×	0.006	RPGRIP1L
detection of mechanical stimulus	1	401.2×	0.006	PKD2
cellular response to osmotic stress	1	401.2×	0.006	PKD2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPGRIP1L	0	0
RPGRIP1	0	0
PKD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PKD2	12	Binding:12

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	RPGRIP1L, RPGRIP1, PKD2

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)
RPGRIP1L	0	—
RPGRIP1	0	—
PKD2	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.