Joubert syndrome and related disorders

disease

On this page

Also known as JSRD

Summary

Joubert syndrome and related disorders (MONDO:0015369) is a disease with 27 cohort genes. The dominant Reactome pathway is Anchoring of the basal body to the plasma membrane (13 cohort genes).

At a glance

Prevalence: >1 / 1000 (North America) [Orphanet-validated]
Cohort genes: 27
ClinVar variants: 253

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1.1	Worldwide	Validated
Point prevalence	>1 / 1000	666.67	North America	Validated
Prevalence at birth	1-9 / 100 000	1	United States	Validated
Prevalence at birth	1-9 / 100 000	1	Netherlands	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome and related disorders
Mondo ID	MONDO:0015369
Orphanet	140874
UMLS	C5679612
MedGen	1826007
GARD	0019931
Is cancer (heuristic)	no

Also known as: Joubert syndrome and related disorders · JSRD

Data availability: 253 ClinVar variants.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › 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

Related subtypes (6): autosomal recessive spinocerebellar ataxia 2, cerebellar ataxia, intellectual disability, and dysequilibrium, Cayman type cerebellar ataxia, autosomal recessive spinocerebellar ataxia 17, CAMOS syndrome, congenital cerebellar ataxia due to RNU12 mutation

Subtypes (4): Joubert syndrome with oculorenal defect, Joubert syndrome with ocular defect, Joubert syndrome with Jeune asphyxiating thoracic dystrophy, COACH syndrome

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

253 retrieved; paginated sample, class counts are floors:

82 pathogenic/likely pathogenic, 78 likely pathogenic, 63 pathogenic, 25 conflicting classifications of pathogenicity, 5 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075243	NM_001134831.2(AHI1):c.1983del (p.Trp662fs)	AHI1	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
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
217534	NM_001134831.2(AHI1):c.1516C>T (p.Arg506Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
217536	NM_001134831.2(AHI1):c.910dup (p.Thr304fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217538	NM_001134831.2(AHI1):c.662C>G (p.Ser221Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
217542	NM_001134831.2(AHI1):c.736A>T (p.Lys246Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
217543	NM_001134831.2(AHI1):c.1260G>A (p.Trp420Ter)	AHI1	Pathogenic	criteria provided, multiple submitters, no conflicts
2907129	NM_001134831.2(AHI1):c.195_202del (p.Asp65fs)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3366410	NC_000006.11:g.(135732683_135748304)_(135752453_135754164)del	AHI1	Pathogenic	criteria provided, single submitter
3366415	NC_000006.11:g.(135732683_135748304)_(135751139_135752345)del	AHI1	Pathogenic	criteria provided, single submitter
3769079	NM_001134831.2(AHI1):c.630_631del (p.Lys211fs)	AHI1	Pathogenic	criteria provided, single submitter
568060	NM_001134831.2(AHI1):c.2105C>T (p.Thr702Met)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
624266	NM_001134831.2(AHI1):c.3032C>G (p.Ser1011Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
661866	NM_001134831.2(AHI1):c.2492+1G>A	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
936055	NM_001134831.2(AHI1):c.484C>T (p.Gln162Ter)	AHI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1993	NM_001174150.2(ARL13B):c.598C>T (p.Arg200Cys)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203408	NM_001174150.2(ARL13B):c.223G>A (p.Gly75Arg)	ARL13B	Pathogenic	criteria provided, multiple submitters, no conflicts
266096	NM_001174150.2(ARL13B):c.599G>A (p.Arg200His)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631931	NM_001174150.2(ARL13B):c.830dup (p.Asn277fs)	ARL13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217556	NM_030578.4(B9D2):c.463G>A (p.Gly155Ser)	B9D2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217558	NM_030578.4(B9D2):c.220C>T (p.Pro74Ser)	B9D2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30931	NM_030578.4(B9D2):c.301A>C (p.Ser101Arg)	B9D2	Pathogenic	criteria provided, single submitter
1453471	NM_001378615.1(CC2D2A):c.2999_3000inv (p.Glu1000Val)	CC2D2A	Pathogenic/Likely 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
2203534	NM_001378615.1(CC2D2A):c.2581G>A (p.Asp861Asn)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343654	NM_014704.4(CEP104):c.1051_1054del (p.Thr351fs)	CEP104	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700581	NM_014704.4(CEP104):c.643C>T (p.Arg215Ter)	CEP104	Pathogenic	criteria provided, single submitter
2691290	NM_014704.4(CEP104):c.1232del (p.Gly411fs)	CEP104	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 72 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM237	Orphanet:220497	Joubert syndrome with renal defect
TMEM237	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM237	Orphanet:475	Isolated Joubert syndrome
TMEM237	Orphanet:564	Meckel syndrome
PMPCA	Orphanet:1170	Autosomal recessive cerebelloparenchymal disorder type 3
KIF14	Orphanet:2512	Autosomal recessive primary microcephaly
KIF14	Orphanet:439897	Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome
KIAA0586	Orphanet:397715	Joubert syndrome with Jeune asphyxiating thoracic dystrophy
KIAA0586	Orphanet:475	Isolated Joubert syndrome
INPP5E	Orphanet:1454	Joubert syndrome with hepatic defect
INPP5E	Orphanet:220493	Joubert syndrome with ocular defect
INPP5E	Orphanet:475	Isolated Joubert syndrome
INPP5E	Orphanet:75858	MORM syndrome
AHI1	Orphanet:220493	Joubert syndrome with ocular defect
AHI1	Orphanet:475	Isolated Joubert syndrome
AHI1	Orphanet:791	Retinitis pigmentosa
B9D1	Orphanet:475	Isolated Joubert syndrome
B9D1	Orphanet:564	Meckel syndrome
TCTN3	Orphanet:2753	Orofaciodigital syndrome type 4
TCTN3	Orphanet:2754	Orofaciodigital syndrome type 6
TCTN3	Orphanet:475	Isolated Joubert syndrome
TCTN3	Orphanet:564	Meckel syndrome
CEP104	Orphanet:475	Isolated Joubert syndrome
CEP104	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
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
ARL13B	Orphanet:475	Isolated Joubert syndrome
TCTN2	Orphanet:475	Isolated Joubert syndrome
TCTN2	Orphanet:564	Meckel syndrome
CPLANE1	Orphanet:2754	Orofaciodigital syndrome type 6
CPLANE1	Orphanet:475	Isolated Joubert syndrome
CPLANE1	Orphanet:65684	Monomelic amyotrophy
TCTN1	Orphanet:475	Isolated Joubert syndrome
TCTN1	Orphanet:564	Meckel syndrome
TMEM138	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM67	Orphanet:140976	RHYNS syndrome
TMEM67	Orphanet:1454	Joubert syndrome with hepatic defect
TMEM67	Orphanet:475	Isolated Joubert syndrome
TMEM67	Orphanet:564	Meckel syndrome
TMEM67	Orphanet:84081	Senior-Boichis syndrome
B9D2	Orphanet:475	Isolated Joubert syndrome
B9D2	Orphanet:564	Meckel syndrome
CEP290	Orphanet:110	Bardet-Biedl syndrome
CEP290	Orphanet:2318	Joubert syndrome with oculorenal defect
CEP290	Orphanet:3156	Senior-Loken syndrome
CEP290	Orphanet:564	Meckel syndrome
CEP290	Orphanet:65	Leber congenital amaurosis
RPGRIP1L	Orphanet:1454	Joubert syndrome with hepatic defect

Cohort genes → proteins

27 cohort genes, 25 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	27

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM237	HGNC:14432	ENSG00000155755	Q96Q45	Transmembrane protein 237	clinvar
PMPCA	HGNC:18667	ENSG00000165688	Q10713	Mitochondrial-processing peptidase subunit alpha	clinvar
KIF14	HGNC:19181	ENSG00000118193	Q15058	Kinesin-like protein KIF14	clinvar
KIAA0586	HGNC:19960	ENSG00000100578	Q9BVV6	Protein TALPID3	clinvar
INPP5E	HGNC:21474	ENSG00000148384	Q9NRR6	Phosphatidylinositol polyphosphate 5-phosphatase type IV	clinvar
AHI1	HGNC:21575	ENSG00000135541	Q8N157	Jouberin	clinvar
B9D1	HGNC:24123	ENSG00000108641	Q9UPM9	B9 domain-containing protein 1	clinvar
NPHP3-AS1	HGNC:24129	ENSG00000248724		NPHP3 antisense RNA 1	clinvar
TCTN3	HGNC:24519	ENSG00000119977	Q6NUS6	Tectonic-3	clinvar
CEP104	HGNC:24866	ENSG00000116198	O60308	Centrosomal protein of 104 kDa	clinvar
TMEM216	HGNC:25018	ENSG00000187049	Q9P0N5	Transmembrane protein 216	clinvar
ARL13B	HGNC:25419	ENSG00000169379	Q3SXY8	ADP-ribosylation factor-like protein 13B	clinvar
TCTN2	HGNC:25774	ENSG00000168778	Q96GX1	Tectonic-2	clinvar
CPLANE1	HGNC:25801	ENSG00000197603	Q9H799	Ciliogenesis and planar polarity effector 1	clinvar
TCTN1	HGNC:26113	ENSG00000204852	Q2MV58	Tectonic-1	clinvar
TMEM138	HGNC:26944	ENSG00000149483	Q9NPI0	Transmembrane protein 138	clinvar
TMEM67	HGNC:28396	ENSG00000164953	Q5HYA8	Meckelin	clinvar
B9D2	HGNC:28636	ENSG00000123810	Q9BPU9	B9 domain-containing protein 2	clinvar
CEP290	HGNC:29021	ENSG00000198707	O15078	Centrosomal protein of 290 kDa	clinvar
RPGRIP1L	HGNC:29168	ENSG00000103494	Q68CZ1	Protein fantom	clinvar
CC2D2A	HGNC:29253	ENSG00000048342	Q9P2K1	Coiled-coil and C2 domain-containing protein 2A	clinvar
LRRCC1	HGNC:29373	ENSG00000133739	Q9C099	Leucine-rich repeat and coiled-coil domain-containing protein 1	clinvar
TMEM231	HGNC:37234	ENSG00000205084	Q9H6L2	Transmembrane protein 231	clinvar
NPHP3-ACAD11	HGNC:48351	ENSG00000274810		NPHP3-ACAD11 readthrough (NMD candidate)	clinvar
MKS1	HGNC:7121	ENSG00000011143	Q9NXB0	Tectonic-like complex member MKS1	clinvar
NPHP1	HGNC:7905	ENSG00000144061	O15259	Nephrocystin-1	clinvar
NPHP3	HGNC:7907	ENSG00000113971	Q7Z494	Nephrocystin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM237	Transmembrane protein 237	Component of the transition zone in primary cilia.
PMPCA	Mitochondrial-processing peptidase subunit alpha	Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
KIF14	Kinesin-like protein KIF14	Microtubule motor protein that binds to microtubules with high affinity through each tubulin heterodimer and has an ATPase activity.
KIAA0586	Protein TALPID3	Required for ciliogenesis and sonic hedgehog/SHH signaling.
INPP5E	Phosphatidylinositol polyphosphate 5-phosphatase type IV	Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bispho…
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.
B9D1	B9 domain-containing protein 1	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.
TCTN3	Tectonic-3	Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition.
CEP104	Centrosomal protein of 104 kDa	Required for ciliogenesis and for structural integrity at the ciliary tip.
TMEM216	Transmembrane protein 216	Essential for primary ciliogenesis and embryonic development, facilitating the activation of Hedgehog (Hh) signaling pathway.
ARL13B	ADP-ribosylation factor-like protein 13B	Cilium-specific protein required to control the microtubule-based, ciliary axoneme structure.
TCTN2	Tectonic-2	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.
CPLANE1	Ciliogenesis and planar polarity effector 1	Involved in ciliogenesis.
TCTN1	Tectonic-1	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.
TMEM138	Transmembrane protein 138	Required for ciliogenesis.
TMEM67	Meckelin	Required for ciliary structure and function.
B9D2	B9 domain-containing protein 2	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.
CEP290	Centrosomal protein of 290 kDa	Involved in early and late steps in cilia formation.
RPGRIP1L	Protein fantom	Negatively regulates signaling through the G-protein coupled thromboxane A2 receptor (TBXA2R).
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.
LRRCC1	Leucine-rich repeat and coiled-coil domain-containing protein 1	Required for the organization of the mitotic spindle.
TMEM231	Transmembrane protein 231	Transmembrane 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.
MKS1	Tectonic-like complex member MKS1	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.
NPHP1	Nephrocystin-1	Together with BCAR1 it may play a role in the control of epithelial cell polarity.
NPHP3	Nephrocystin-3	Required for normal ciliary development and function.

Protein-family classification

Druggable: 3 · Difficult: 4 · Unknown: 20 · Druggable fraction: 0.11

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	20	1.3×	0.203
Protease	2	2.7×	0.339
Scaffold/PPI	3	1.9×	0.339
Enzyme (other)	1	0.4×	0.969
Transcription factor	1	0.3×	0.969

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM237	Other/Unknown	no		TMEM237
PMPCA	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16
KIF14	Other/Unknown	no		FHA_dom, Kinesin_motor_dom, SMAD_FHA_dom_sf
KIAA0586	Other/Unknown	no		TALPID3
INPP5E	Enzyme (other)	yes	3.1.3.36	IPPc, Endo/exonu/phosph_ase_sf, INPP5E
AHI1	Scaffold/PPI	no		SH3_domain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
B9D1	Other/Unknown	no		C2_B9-type_dom
NPHP3-AS1	Other/Unknown	no
TCTN3	Other/Unknown	no		TCTN1-3_dom, TCTN1-3, TCTN1-3_N
CEP104	Transcription factor	no		Galactose-bd-like_sf, ARM-like, ARM-type_fold
TMEM216	Other/Unknown	no		Uncharacterised_TM-17
ARL13B	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, P-loop_NTPase
TCTN2	Other/Unknown	no		TCTN1-3_dom, TCTN1-3, TCTN1-3_N
CPLANE1	Scaffold/PPI	no		CPLANE1, WD40_repeat_dom_sf
TCTN1	Other/Unknown	no		TCTN1-3_dom, TCTN1-3, TCTN1-3_N
TMEM138	Other/Unknown	no		TM_138
TMEM67	Other/Unknown	no		Growth_fac_rcpt_cys_sf, Meckelin
B9D2	Other/Unknown	no		C2_B9-type_dom
CEP290	Other/Unknown	no		Cep290, Cep209_CC5
RPGRIP1L	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
CC2D2A	Protease	yes		C2_dom, CC2D2AN-C2, C2_domain_sf
LRRCC1	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_4, LRR_dom_sf
TMEM231	Other/Unknown	no		TMEM231
NPHP3-ACAD11	Other/Unknown	no
MKS1	Other/Unknown	no		C2_B9-type_dom
NPHP1	Scaffold/PPI	no		SH3_domain, NPHP1_SH3, SH3-like_dom_sf
NPHP3	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

25 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)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	9
calcaneal tendon	7
male germ line stem cell (sensu Vertebrata) in testis	6
secondary oocyte	5
bronchial epithelial cell	5
olfactory segment of nasal mucosa	4
ventricular zone	3
adenohypophysis	3
buccal mucosa cell	3
adrenal tissue	2
left testis	2
pituitary gland	2
sural nerve	2
primordial germ cell in gonad	2
bronchus	2
left ovary	2
apex of heart	1
right lobe of liver	1
endometrium epithelium	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM237	250	ubiquitous	marker	calcaneal tendon, adrenal tissue, ventricular zone
PMPCA	276	ubiquitous	marker	right lobe of liver, adrenal tissue, apex of heart
KIF14	144	ubiquitous	marker	secondary oocyte, endometrium epithelium, trabecular bone tissue
KIAA0586	247	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
INPP5E	279	ubiquitous	yes	right uterine tube, secondary oocyte, oocyte
AHI1	276	ubiquitous	marker	pituitary gland, calcaneal tendon, right hemisphere of cerebellum
B9D1	224	ubiquitous	marker	right uterine tube, adenohypophysis, left testis
NPHP3-AS1	59		marker	sural nerve, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
TCTN3	267	ubiquitous	marker	corpus epididymis, decidua, stromal cell of endometrium
CEP104	284	ubiquitous	marker	secondary oocyte, buccal mucosa cell, sperm
TMEM216	239	ubiquitous	marker	primordial germ cell in gonad, adenohypophysis, pituitary gland
ARL13B	237	ubiquitous	marker	secondary oocyte, calcaneal tendon, bronchial epithelial cell
TCTN2	218	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, olfactory bulb
CPLANE1	195	ubiquitous	marker	sural nerve, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis
TCTN1	230	ubiquitous	marker	right uterine tube, adenohypophysis, olfactory segment of nasal mucosa
TMEM138	245	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
TMEM67	203	ubiquitous	marker	buccal mucosa cell, right uterine tube, calcaneal tendon
B9D2	138	ubiquitous	marker	right uterine tube, blood, olfactory segment of nasal mucosa
CEP290	278	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone
RPGRIP1L	207	ubiquitous	marker	bronchial epithelial cell, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
CC2D2A	247	ubiquitous	marker	right uterine tube, bronchial epithelial cell, bronchus
LRRCC1	189	ubiquitous	marker	calcaneal tendon, ventricular zone, C1 segment of cervical spinal cord
TMEM231	257	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
NPHP3-ACAD11	133	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, endometrium
MKS1	182	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, left ovary
NPHP1	193	ubiquitous	marker	right uterine tube, bronchial epithelial cell, olfactory segment of nasal mucosa
NPHP3	254	ubiquitous	marker	superficial temporal artery, layer of synovial tissue, left ovary

Protein interactions among cohort

Intra-cohort edges: 144.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF14	6,868
PMPCA	3,679
CEP290	2,778
ARL13B	2,558
NPHP1	2,302
NPHP3	2,275
TMEM237	2,169
RPGRIP1L	2,027
AHI1	1,681
KIAA0586	1,405

Intra-cohort edges

A	B	Sources
AHI1	ARL13B	string_interaction
AHI1	B9D1	string_interaction
AHI1	B9D2	string_interaction
AHI1	CC2D2A	biogrid_interaction, intact, string_interaction
AHI1	CEP290	string_interaction
AHI1	CPLANE1	string_interaction
AHI1	NPHP1	intact, string_interaction
AHI1	RPGRIP1L	string_interaction
AHI1	TCTN1	string_interaction
AHI1	TCTN2	string_interaction
AHI1	TCTN3	string_interaction
AHI1	TMEM138	string_interaction
AHI1	TMEM216	string_interaction
AHI1	TMEM231	string_interaction
AHI1	TMEM67	string_interaction
ARL13B	CC2D2A	string_interaction
ARL13B	CEP290	string_interaction
ARL13B	INPP5E	string_interaction
ARL13B	NPHP1	string_interaction
ARL13B	RPGRIP1L	string_interaction
ARL13B	TMEM216	string_interaction
ARL13B	TMEM67	string_interaction
B9D1	B9D2	biogrid_interaction, intact, string_interaction
B9D1	CC2D2A	biogrid_interaction, intact, string_interaction
B9D1	CEP290	string_interaction
B9D1	MKS1	biogrid_interaction, intact, string_interaction
B9D1	NPHP1	string_interaction
B9D1	RPGRIP1L	string_interaction
B9D1	TCTN1	intact, string_interaction
B9D1	TCTN2	intact, string_interaction
B9D1	TCTN3	string_interaction
B9D1	TMEM138	string_interaction
B9D1	TMEM216	string_interaction
B9D1	TMEM231	biogrid_interaction, intact, string_interaction
B9D1	TMEM237	string_interaction
B9D1	TMEM67	string_interaction
B9D2	CC2D2A	biogrid_interaction, intact, string_interaction
B9D2	CEP290	string_interaction
B9D2	MKS1	biogrid_interaction, intact
B9D2	NPHP1	string_interaction
B9D2	RPGRIP1L	string_interaction
B9D2	TCTN1	intact, string_interaction
B9D2	TCTN2	string_interaction
B9D2	TCTN3	intact, string_interaction
B9D2	TMEM216	string_interaction
B9D2	TMEM231	biogrid_interaction, intact, string_interaction
B9D2	TMEM237	string_interaction
B9D2	TMEM67	string_interaction
CC2D2A	CEP290	string_interaction
CC2D2A	CPLANE1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 18 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CEP104	O60308	2
NPHP1	O15259	2
INPP5E	Q9NRR6	1
AHI1	Q8N157	1
TMEM67	Q5HYA8	1
RPGRIP1L	Q68CZ1	1
NPHP3	Q7Z494	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B9D2	Q9BPU9	89.79
TMEM216	Q9P0N5	89.18
TMEM231	Q9H6L2	88.65
PMPCA	Q10713	88.46
TMEM138	Q9NPI0	86.42
B9D1	Q9UPM9	83.05
TCTN1	Q2MV58	78.10
TCTN2	Q96GX1	74.71
LRRCC1	Q9C099	74.43
MKS1	Q9NXB0	74.05
ARL13B	Q3SXY8	72.92
TCTN3	Q6NUS6	71.49
CC2D2A	Q9P2K1	69.46
KIF14	Q15058	65.68
TMEM237	Q96Q45	63.79
CEP290	O15078	60.90
KIAA0586	Q9BVV6	47.61
CPLANE1	Q9H799

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 62. Enrichment computed across 27 evidence-associated genes (18 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 18 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	13	81.7×	5e-22	AHI1, B9D1, TCTN3, TMEM216, TCTN2, TCTN1, TMEM67, B9D2 (+5 more)
Cilium Assembly	12	72.5×	1e-19	INPP5E, AHI1, B9D1, TCTN3, ARL13B, TCTN2, TCTN1, TMEM67 (+4 more)
Organelle biogenesis and maintenance	12	44.0×	4e-17	INPP5E, AHI1, B9D1, TCTN3, ARL13B, TCTN2, TCTN1, TMEM67 (+4 more)
ARL13B-mediated ciliary trafficking of INPP5E	2	423.0×	1e-04	INPP5E, ARL13B
Cargo trafficking to the periciliary membrane	2	27.6×	0.029	INPP5E, ARL13B
Hedgehog ‘off’ state	2	19.8×	0.046	RPGRIP1L, MKS1
Trafficking of myristoylated proteins to the cilium	1	126.9×	0.070	NPHP3
Signaling by Rho GTPases	3	5.7×	0.106	KIF14, ARL13B, B9D2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	3	5.6×	0.106	KIF14, ARL13B, B9D2
Synthesis of PIPs at the Golgi membrane	1	35.2×	0.123	INPP5E
Processing of SMDT1	1	35.2×	0.123	PMPCA
RHO GTPases activate CIT	1	33.4×	0.123	KIF14
Mitochondrial calcium ion transport	1	30.2×	0.123	PMPCA
Chaperone Mediated Autophagy	1	27.6×	0.123	ARL13B
Mitotic Prometaphase	2	7.7×	0.123	B9D2, CEP290
RHO GTPase Effectors	2	7.5×	0.123	KIF14, B9D2
M Phase	2	7.3×	0.123	B9D2, CEP290
RHO GTPase cycle	2	6.7×	0.123	KIF14, ARL13B
PI Metabolism	1	19.8×	0.159	INPP5E
Late endosomal microautophagy	1	18.1×	0.159	ARL13B
Cell Cycle, Mitotic	2	5.3×	0.159	B9D2, CEP290
Selective autophagy	1	15.5×	0.167	ARL13B
RND1 GTPase cycle	1	14.8×	0.167	KIF14
RND2 GTPase cycle	1	14.4×	0.167	KIF14
Centrosome maturation	1	14.1×	0.167	CEP290
Aggrephagy	1	13.8×	0.167	ARL13B
Phospholipid metabolism	1	11.1×	0.173	INPP5E
RHOJ GTPase cycle	1	11.1×	0.173	ARL13B
Amplification of signal from the kinetochores	1	10.9×	0.173	B9D2
Protein localization	1	10.6×	0.173	PMPCA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 24 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cilium assembly	19	58.3×	9e-30	TMEM237, KIAA0586, INPP5E, AHI1, B9D1, TCTN3, TMEM216, ARL13B (+11 more)
non-motile cilium assembly	7	84.7×	9e-11	TMEM216, ARL13B, CEP290, RPGRIP1L, CC2D2A, MKS1, NPHP3
smoothened signaling pathway	7	52.9×	2e-09	KIAA0586, B9D1, TCTN3, ARL13B, TCTN2, CC2D2A, TMEM231
protein localization to ciliary transition zone	3	300.9×	3e-06	TCTN2, TCTN1, CC2D2A
camera-type eye development	4	59.8×	2e-05	B9D1, CEP290, CC2D2A, TMEM231
determination of left/right symmetry	4	42.6×	5e-05	RPGRIP1L, CC2D2A, MKS1, NPHP3
regulation of smoothened signaling pathway	3	78.0×	1e-04	TCTN1, RPGRIP1L, MKS1
motile cilium assembly	3	72.6×	2e-04	AHI1, CC2D2A, MKS1
regulation of Wnt signaling pathway, planar cell polarity pathway	2	280.9×	3e-04	MKS1, NPHP3
kidney development	4	23.4×	3e-04	CEP290, RPGRIP1L, CC2D2A, NPHP3
neural tube patterning	2	234.1×	4e-04	ARL13B, RPGRIP1L
regulation of establishment of protein localization	2	200.6×	5e-04	KIAA0586, CEP290
embryonic digit morphogenesis	3	37.6×	7e-04	B9D1, TMEM231, MKS1
neuroepithelial cell differentiation	2	127.7×	0.001	B9D1, TMEM231
vasculature development	2	93.6×	0.002	B9D1, TMEM231
in utero embryonic development	4	12.0×	0.003	B9D1, TCTN1, RPGRIP1L, TMEM231
dorsal/ventral neural tube patterning	2	66.9×	0.003	TCTN1, MKS1
embryonic brain development	2	66.9×	0.003	CC2D2A, MKS1
olfactory bulb development	2	63.8×	0.003	KIF14, RPGRIP1L
smoothened signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	702.2×	0.008	MKS1
cerebellar granular layer structural organization	1	702.2×	0.008	KIF14
interneuron migration from the subpallium to the cortex	1	702.2×	0.008	ARL13B
central nervous system interneuron axonogenesis	1	702.2×	0.008	TCTN1
determination of intestine left/right asymmetry	1	702.2×	0.008	NPHP3
determination of stomach left/right asymmetry	1	702.2×	0.008	NPHP3
regulation of cell maturation	1	702.2×	0.008	KIF14
establishment or maintenance of cell polarity	2	33.4×	0.009	RPGRIP1L, NPHP3
photoreceptor cell maintenance	2	29.9×	0.010	TMEM216, NPHP3
cerebellar Purkinje cell layer structural organization	1	351.1×	0.013	KIF14
convergent extension involved in gastrulation	1	351.1×	0.013	NPHP3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 27

Druggability breadth: 2 of 27 evidence-associated genes (7%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMEM237	0	0
PMPCA	0	0
KIF14	0	0
KIAA0586	0	0
INPP5E	0	0
AHI1	0	0
B9D1	0	0
NPHP3-AS1	0	0
TCTN3	0	0
CEP104	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PMPCA	1	Binding:1
KIF14	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PMPCA	3.4.24.64	mitochondrial processing peptidase
INPP5E	3.1.3.36	phosphoinositide 5-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 26; 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	1	INPP5E
D	Druggable family + AlphaFold only, no drug	2	PMPCA, CC2D2A
E	Difficult family or no structure, no drug	24	TMEM237, KIF14, KIAA0586, AHI1, B9D1, NPHP3-AS1, TCTN3, CEP104, TMEM216, ARL13B (+14 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM237	0	—
PMPCA	1	—
KIF14	1	—
KIAA0586	0	—
INPP5E	0	—
AHI1	0	—
B9D1	0	—
NPHP3-AS1	0	—
TCTN3	0	—
CEP104	0	—
TMEM216	0	—
ARL13B	0	—
TCTN2	0	—
CPLANE1	0	—
TCTN1	0	—
TMEM138	0	—
TMEM67	0	—
B9D2	0	—
CEP290	0	—
RPGRIP1L	0	—
CC2D2A	0	—
LRRCC1	0	—
TMEM231	0	—
NPHP3-ACAD11	0	—
MKS1	0	—
NPHP1	0	—
NPHP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: TMEM237, PMPCA, KIF14, KIAA0586, INPP5E, AHI1, B9D1, NPHP3-AS1, TCTN3, CEP104, TMEM216, ARL13B, TCTN2, CPLANE1, TCTN1, TMEM138, TMEM67, B9D2, CEP290, RPGRIP1L, CC2D2A, LRRCC1, TMEM231, MKS1, NPHP1, NPHP3