Joubert syndrome 3

Summary

Joubert syndrome 3 (MONDO:0012078) is a disease caused by AHI1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: AHI1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 477

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 3
Mondo ID	MONDO:0012078
MeSH	C536295
OMIM	608629
DOID	DOID:0110998
NCIT	C148259
UMLS	C1837713
MedGen	332931
GARD	0015435
Is cancer (heuristic)	no

Also known as: AHI1 Joubert syndrome · JBTS3 · Joubert syndrome 3 · Joubert syndrome caused by mutation in AHI1 · Joubert syndrome type 3

Data availability: 477 ClinVar variants · 6 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome with ocular defect › Joubert syndrome 3

Related subtypes (4): Joubert syndrome 14, Joubert syndrome 15, Joubert syndrome 20, Joubert syndrome 28

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

477 retrieved; paginated sample, class counts are floors:

231 uncertain significance, 67 conflicting classifications of pathogenicity, 47 pathogenic/likely pathogenic, 42 pathogenic, 35 likely pathogenic, 22 likely benign, 20 benign/likely benign, 13 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029630	NM_001134831.2(AHI1):c.2361G>A (p.Trp787Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
1065721	NM_001134831.2(AHI1):c.3235C>T (p.Arg1079Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070164	NM_001134831.2(AHI1):c.1583C>A (p.Ser528Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073454	NM_001134831.2(AHI1):c.1166C>G (p.Ser389Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1213815	NM_001134831.2(AHI1):c.430del (p.Glu144fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322959	NM_001134831.2(AHI1):c.3059dup (p.Asn1020fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322964	NM_001134831.2(AHI1):c.313C>T (p.Gln105Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322966	NM_001134831.2(AHI1):c.1044C>A (p.Tyr348Ter)	AHI1	Pathogenic	criteria provided, single submitter
1322971	NM_001134831.2(AHI1):c.1369_1373del (p.Asp456_Glu457insTer)	AHI1	Pathogenic	criteria provided, single submitter
1326575	NM_001134831.2(AHI1):c.630_633del (p.Lys210fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363432	NM_001134831.2(AHI1):c.2233del (p.Ser745fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1370876	NM_001134831.2(AHI1):c.1799_1802del (p.Lys600fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1422218	NM_001134831.2(AHI1):c.1420del (p.Ile474fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453940	NM_001134831.2(AHI1):c.478A>T (p.Lys160Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458722	NM_001134831.2(AHI1):c.533_534del (p.Glu178fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459367	NM_001134831.2(AHI1):c.1981T>C (p.Ser661Pro)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156382	NM_001134831.2(AHI1):c.2174G>A (p.Trp725Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156383	NM_001134831.2(AHI1):c.2598_2604del (p.Ile866fs)	AHI1	Pathogenic	no assertion criteria provided
2010	NM_001134831.2(AHI1):c.1051C>T (p.Arg351Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
2011	NM_001134831.2(AHI1):c.1303C>T (p.Arg435Ter)	AHI1	Pathogenic	criteria provided, single submitter
2012	NM_001134831.2(AHI1):c.1328T>A (p.Val443Asp)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2014	NM_001134831.2(AHI1):c.1765C>T (p.Arg589Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
2016	NM_001134831.2(AHI1):c.2368_2369insT (p.Asn790fs)	AHI1	Pathogenic	no assertion criteria provided
210113	NM_001134831.2(AHI1):c.1861G>T (p.Gly621Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2168890	NM_001134831.2(AHI1):c.101del (p.Lys34fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217522	NM_001134831.2(AHI1):c.2036+1G>T	AHI1	Pathogenic	criteria provided, single submitter
217523	NM_001134831.2(AHI1):c.1267C>T (p.Gln423Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
217524	NM_001134831.2(AHI1):c.2495T>G (p.Leu832Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217525	NM_001134831.2(AHI1):c.2212C>T (p.Arg738Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
217526	NM_001134831.2(AHI1):c.1897_1898dup (p.Tyr634fs)	AHI1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
AHI1	Definitive	Autosomal recessive	Joubert syndrome 3	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AHI1	Orphanet:220493	Joubert syndrome with ocular defect
AHI1	Orphanet:475	Isolated Joubert syndrome
AHI1	Orphanet:791	Retinitis pigmentosa
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
NIN	Orphanet:319675	Microcephalic primordial dwarfism, Dauber type
NIN	Orphanet:808	Seckel syndrome

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
AHI1	HGNC:21575	ENSG00000135541	Q8N157	Jouberin	gencc,clinvar
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	clinvar
NIN	HGNC:14906	ENSG00000100503	Q8N4C6	Ninein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AHI1	Jouberin	Involved in vesicle trafficking and required for ciliogenesis, formation of primary non-motile cilium, and recruitment of RAB8A to the basal body of primary cilium.
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
NIN	Ninein	Centrosomal protein required in the positioning and anchorage of the microtubule minus-end in epithelial cells.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	2	11.5×	0.019
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AHI1	Scaffold/PPI	no		SH3_domain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
NIN	Other/Unknown	no		EF_hand_dom, 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
calcaneal tendon	1
pituitary gland	1
right hemisphere of cerebellum	1
colonic epithelium	1
jejunal mucosa	1
tendon of biceps brachii	1
buccal mucosa cell	1
cardiac muscle of right atrium	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AHI1	276	ubiquitous	marker	pituitary gland, calcaneal tendon, right hemisphere of cerebellum
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
NIN	253	ubiquitous	marker	oviduct epithelium, buccal mucosa cell, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOS1	3,625
NIN	2,525
AHI1	1,681

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SOS1	Q07889	91
AHI1	Q8N157	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NIN	Q8N4C6	64.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 136. 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
Downstream signaling of activated FGFR2	1	2855.0×	0.008	SOS1
Downstream signaling of activated FGFR3	1	2855.0×	0.008	SOS1
Downstream signaling of activated FGFR4	1	1903.3×	0.008	SOS1
Signaling by ERBB2 in Cancer	1	1142.0×	0.008	SOS1
Signaling by EGFRvIII in Cancer	1	1142.0×	0.008	SOS1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1	951.7×	0.008	SOS1
Signaling by NTRK2 (TRKB)	1	815.7×	0.008	SOS1
Signaling by PDGFR in disease	1	815.7×	0.008	SOS1
SOS-mediated signalling	1	713.8×	0.008	SOS1
IGF1R signaling cascade	1	713.8×	0.008	SOS1
Activated NTRK3 signals through RAS	1	634.4×	0.008	SOS1
Signaling by EGFR in Cancer	1	571.0×	0.008	SOS1
EGFR Transactivation by Gastrin	1	571.0×	0.008	SOS1
SHC-related events triggered by IGF1R	1	571.0×	0.008	SOS1
Signaling by FGFR3	1	571.0×	0.008	SOS1
Activated NTRK2 signals through RAS	1	571.0×	0.008	SOS1
Signaling by NTRK3 (TRKC)	1	571.0×	0.008	SOS1
Signaling by KIT in disease	1	571.0×	0.008	SOS1
FLT3 signaling in disease	1	571.0×	0.008	SOS1
IRS-mediated signalling	1	519.1×	0.008	SOS1
IRS-related events triggered by IGF1R	1	519.1×	0.008	SOS1
Signaling by FGFR4	1	519.1×	0.008	SOS1
Signal attenuation	1	519.1×	0.008	SOS1
MET activates RAS signaling	1	519.1×	0.008	SOS1
Signaling by Erythropoietin	1	519.1×	0.008	SOS1
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	475.8×	0.008	SOS1
Signaling by FGFR4 in disease	1	475.8×	0.008	SOS1
Activated NTRK2 signals through FRS2 and FRS3	1	475.8×	0.008	SOS1
Constitutive Signaling by Overexpressed ERBB2	1	475.8×	0.008	SOS1
Signaling by Insulin receptor	1	439.2×	0.008	SOS1

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
centrosome-templated microtubule nucleation	1	2808.7×	0.007	NIN
midbrain morphogenesis	1	1404.3×	0.007	SOS1
vitellogenesis	1	1123.5×	0.007	SOS1
regulation of pro-B cell differentiation	1	1123.5×	0.007	SOS1
cardiac atrium morphogenesis	1	936.2×	0.007	SOS1
corpus callosum morphogenesis	1	802.5×	0.007	NIN
corticospinal tract morphogenesis	1	802.5×	0.007	NIN
regulation of T cell differentiation in thymus	1	802.5×	0.007	SOS1
intracellular protein localization	2	69.8×	0.007	AHI1, NIN
pericardium morphogenesis	1	702.2×	0.007	SOS1
heart trabecula morphogenesis	1	624.1×	0.007	SOS1
microtubule anchoring at centrosome	1	468.1×	0.007	NIN
regulation of behavior	1	468.1×	0.007	AHI1
centriole-centriole cohesion	1	432.1×	0.007	NIN
collateral sprouting	1	401.2×	0.007	NIN
Schwann cell development	1	351.1×	0.007	SOS1
photoreceptor cell outer segment organization	1	351.1×	0.007	AHI1
regulation of T cell proliferation	1	351.1×	0.007	SOS1
neurotrophin TRK receptor signaling pathway	1	351.1×	0.007	SOS1
eyelid development in camera-type eye	1	351.1×	0.007	SOS1
centrosome localization	1	295.6×	0.008	NIN
blood vessel morphogenesis	1	267.5×	0.009	SOS1
Fc-epsilon receptor signaling pathway	1	244.2×	0.009	SOS1
positive regulation of receptor internalization	1	234.1×	0.009	AHI1
positive regulation of Rac protein signal transduction	1	216.1×	0.010	SOS1
leukocyte migration	1	208.1×	0.010	SOS1
motile cilium assembly	1	193.7×	0.010	AHI1
positive regulation of axonogenesis	1	193.7×	0.010	NIN
B cell homeostasis	1	187.2×	0.010	SOS1
positive regulation of epidermal growth factor receptor signaling pathway	1	165.2×	0.010	SOS1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
SOS1	IDARUBICIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOS1	5	4
AHI1	0	0
NIN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
MRTX-0902	1	SOS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SOS1	421	Binding:409, Functional:12

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SOS1	421

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

5 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)
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
MRTX-0902	1	SOS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SOS1
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	2	AHI1, NIN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AHI1	0	—
NIN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.