Ellis-van Creveld syndrome

Summary

Ellis-van Creveld syndrome (MONDO:0009162) is a disease caused by variants in EVC and EVC2, with 10 cohort genes. The dominant Reactome pathway is Hedgehog ‘off’ state (4 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: EVC (GenCC Definitive), EVC2 (GenCC Definitive)
• Cohort genes: 10
• ClinVar variants: 3,779
• Phenotypes (HPO): 51

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.4	Europe	Validated
Prevalence at birth	>1 / 1000	500	Specific population	Validated
Prevalence at birth	1-9 / 100 000	1.1	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0001161	Hand polydactyly	Very frequent (80-99%)
HP:0001231	Abnormal fingernail morphology	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001595	Abnormality of the hair	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0001654	Abnormal heart valve morphology	Very frequent (80-99%)
HP:0001800	Hypoplastic toenails	Very frequent (80-99%)
HP:0001829	Foot polydactyly	Very frequent (80-99%)
HP:0002164	Nail dysplasia	Very frequent (80-99%)
HP:0002857	Genu valgum	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0006695	Atrioventricular canal defect	Very frequent (80-99%)
HP:0008921	Neonatal short-limb short stature	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0010306	Short thorax	Very frequent (80-99%)
HP:0011830	Abnormal oral mucosa morphology	Very frequent (80-99%)
HP:0030680	Abnormal cardiovascular system morphology	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000039	Epispadias	Frequent (30-79%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000069	Abnormality of the ureter	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Frequent (30-79%)
HP:0000190	Abnormal oral frenulum morphology	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000668	Hypodontia	Frequent (30-79%)
HP:0000691	Microdontia	Frequent (30-79%)
HP:0001241	Capitate-hamate fusion	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001651	Dextrocardia	Frequent (30-79%)
HP:0001696	Situs inversus totalis	Frequent (30-79%)
HP:0002644	Abnormality of pelvic girdle bone morphology	Frequent (30-79%)
HP:0006703	Aplasia/Hypoplasia of the lungs	Frequent (30-79%)
HP:0011065	Conical incisor	Frequent (30-79%)
HP:0000008	Abnormal morphology of female internal genitalia	Occasional (5-29%)
HP:0000072	Hydroureter	Occasional (5-29%)
HP:0000233	Thin vermilion border	Occasional (5-29%)
HP:0000684	Delayed eruption of teeth	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0002097	Emphysema	Occasional (5-29%)
HP:0002488	Acute leukemia	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0002967	Cubitus valgus	Occasional (5-29%)
HP:0005048	Synostosis of carpal bones	Occasional (5-29%)
HP:0005561	Abnormality of bone marrow cell morphology	Occasional (5-29%)
HP:0008678	Renal hypoplasia/aplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ellis-van Creveld syndrome
Mondo ID	MONDO:0009162
MeSH	D004613
OMIM	225500
Orphanet	289
DOID	DOID:12714
ICD-10-CM	Q77.6
NCIT	C84684
SNOMED CT	62501005
UMLS	C0013903
MedGen	8584
GARD	0001301
MedDRA	10008724
NORD	1083
Is cancer (heuristic)	no

Also known as: Chondroectodermal dysplasia · Ellis Van Creveld Syndrome · Ellis Van Creveld syndrome · Ellis-VAN Creveld syndrome · Ellis-van Creveld syndrome · EVC · mesodermic dysplasia · Mesoectodermal dysplasia

Data availability: 3,779 ClinVar variants · 14 GenCC gene-disease records · 14 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › Ellis-van Creveld syndrome

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (1): Jeune syndrome situs inversus

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:

402 likely benign, 97 uncertain significance, 57 pathogenic, 12 pathogenic/likely pathogenic, 11 likely pathogenic, 10 benign, 9 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073308	NC_000004.11:g.(?2200251)(5710240_?)del	ADRA2C	Pathogenic	criteria provided, single submitter
1013604	NM_153717.3(EVC):c.37_38del (p.Arg13fs)	EVC	Pathogenic	criteria provided, multiple submitters, no conflicts
1066868	NM_153717.3(EVC):c.175-2A>G	EVC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068990	NM_153717.3(EVC):c.2561+1dup	EVC	Pathogenic	criteria provided, single submitter
1069685	NC_000004.11:g.(?5798739)(5798969_?)del	EVC	Pathogenic	criteria provided, single submitter
1069686	NC_000004.11:g.(?5809918)(5811348_?)del	EVC	Pathogenic	criteria provided, single submitter
1069687	NC_000004.11:g.(?5754553)(5755670_?)del	EVC	Pathogenic	criteria provided, single submitter
1069725	NM_153717.3(EVC):c.2145_2146insGCCC (p.Gln716fs)	EVC	Pathogenic	criteria provided, single submitter
1069802	NM_153717.3(EVC):c.720dup (p.Lys241Ter)	EVC	Pathogenic	criteria provided, single submitter
1070697	NM_153717.3(EVC):c.539C>A (p.Ser180Ter)	EVC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072443	NM_153717.3(EVC):c.1047_1048del (p.Arg349fs)	EVC	Pathogenic	criteria provided, single submitter
1072476	NM_153717.3(EVC):c.1494del (p.Arg498fs)	EVC	Pathogenic	criteria provided, single submitter
1072936	NM_153717.3(EVC):c.1021C>T (p.Gln341Ter)	EVC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073032	NM_153717.3(EVC):c.1228G>T (p.Glu410Ter)	EVC	Pathogenic	criteria provided, single submitter
1073898	NM_153717.3(EVC):c.2545C>T (p.Gln849Ter)	EVC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074895	NM_153717.3(EVC):c.1290_1291delinsAA (p.Trp430_Gln431delinsTer)	EVC	Pathogenic	criteria provided, single submitter
1074980	NM_153717.3(EVC):c.1746_1747del (p.Phe583fs)	EVC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210401	NM_153717.3(EVC):c.1750del (p.Gln584fs)	EVC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322838	NM_153717.3(EVC):c.1783_1886+40del	EVC	Pathogenic	criteria provided, multiple submitters, no conflicts
1332830	NM_153717.3(EVC):c.1327C>T (p.Arg443Ter)	EVC	Pathogenic	criteria provided, multiple submitters, no conflicts
1370178	NM_153717.3(EVC):c.788C>G (p.Ser263Ter)	EVC	Pathogenic	criteria provided, single submitter
1371302	NM_153717.3(EVC):c.338dup (p.Ala114fs)	EVC	Pathogenic	criteria provided, single submitter
1374481	NM_153717.3(EVC):c.673del (p.Asp225fs)	EVC	Pathogenic	criteria provided, single submitter
1379233	NM_153717.3(EVC):c.2698C>T (p.Gln900Ter)	EVC	Pathogenic	criteria provided, single submitter
1383767	NM_153717.3(EVC):c.2488G>T (p.Glu830Ter)	EVC	Pathogenic	criteria provided, single submitter
1385574	NM_153717.3(EVC):c.2705del (p.Phe902fs)	EVC	Pathogenic	criteria provided, single submitter
1390075	NM_153717.3(EVC):c.1324C>T (p.Gln442Ter)	EVC	Pathogenic	criteria provided, single submitter
1393169	NM_153717.3(EVC):c.90del (p.Ala31fs)	EVC	Pathogenic	criteria provided, single submitter
1396608	NM_153717.3(EVC):c.583del (p.Arg194_Val195insTer)	EVC	Pathogenic	criteria provided, single submitter
1430455	NC_000004.11:g.(?5803667)(5806578_?)del	EVC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 39 · Orphanet: 19 · 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
EVC	Definitive	Autosomal recessive	Ellis-van Creveld syndrome	7
EVC2	Definitive	Autosomal recessive	Ellis-van Creveld syndrome	10
DYNC2LI1	Supportive	Autosomal recessive	Ellis-van Creveld syndrome	5
GLI1	Supportive	Autosomal recessive	Ellis-van Creveld syndrome	8
PRKACA	Supportive	Autosomal recessive	Ellis-van Creveld syndrome	5
PRKACB	Supportive	Autosomal recessive	Ellis-van Creveld syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EVC2	Orphanet:289	Ellis Van Creveld syndrome
EVC2	Orphanet:952	Acrofacial dysostosis, Weyers type
EVC	Orphanet:289	Ellis Van Creveld syndrome
EVC	Orphanet:952	Acrofacial dysostosis, Weyers type
DYNC2LI1	Orphanet:289	Ellis Van Creveld syndrome
DYNC2LI1	Orphanet:474	Jeune syndrome
GLI1	Orphanet:289	Ellis Van Creveld syndrome
GLI1	Orphanet:93334	Postaxial polydactyly type A
GLI1	Orphanet:93335	Postaxial polydactyly type B
GLI1	Orphanet:93339	Polydactyly of a biphalangeal thumb and/or hallux
PRKACA	Orphanet:289	Ellis Van Creveld syndrome
PRKACA	Orphanet:401920	Fibrolamellar hepatocellular carcinoma
PRKACB	Orphanet:289	Ellis Van Creveld syndrome
IFT54	Orphanet:3156	Senior-Loken syndrome
IFT54	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
CCDC39	Orphanet:244	Primary ciliary dyskinesia
WDR35	Orphanet:1515	Cranioectodermal dysplasia
WDR35	Orphanet:498497	Short rib-polydactyly syndrome type 5
WDR35	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EVC2	HGNC:19747	ENSG00000173040	Q86UK5	Limbin	gencc,clinvar
EVC	HGNC:3497	ENSG00000072840	P57679	EvC complex member EVC	gencc,clinvar
DYNC2LI1	HGNC:24595	ENSG00000138036	Q8TCX1	Cytoplasmic dynein 2 light intermediate chain 1	gencc
GLI1	HGNC:4317	ENSG00000111087	P08151	Zinc finger protein GLI1	gencc
PRKACA	HGNC:9380	ENSG00000072062	P17612	cAMP-dependent protein kinase catalytic subunit alpha	gencc
PRKACB	HGNC:9381	ENSG00000142875	P22694	cAMP-dependent protein kinase catalytic subunit beta	gencc
IFT54	HGNC:17861	ENSG00000204104	Q8TDR0	TRAF3-interacting protein 1	clinvar
CCDC39	HGNC:25244	ENSG00000284862	Q9UFE4	Coiled-coil domain-containing protein 39	clinvar
ADRA2C	HGNC:283	ENSG00000184160	P18825	Alpha-2C adrenergic receptor	clinvar
WDR35	HGNC:29250	ENSG00000118965	Q9P2L0	WD repeat-containing protein 35	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EVC2	Limbin	Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.
EVC	EvC complex member EVC	Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.
DYNC2LI1	Cytoplasmic dynein 2 light intermediate chain 1	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the i…
GLI1	Zinc finger protein GLI1	Acts as a transcriptional activator.
PRKACA	cAMP-dependent protein kinase catalytic subunit alpha	Phosphorylates a large number of substrates in the cytoplasm and the nucleus.
PRKACB	cAMP-dependent protein kinase catalytic subunit beta	Mediates cAMP-dependent signaling triggered by receptor binding to GPCRs.
IFT54	TRAF3-interacting protein 1	Plays an inhibitory role on IL13 signaling by binding to IL13RA1.
CCDC39	Coiled-coil domain-containing protein 39	Required for assembly of dynein regulatory complex (DRC) and inner dynein arm (IDA) complexes, which are responsible for ciliary beat regulation, thereby playing a central role in motility in cilia and flagella.
ADRA2C	Alpha-2C adrenergic receptor	Alpha-2 adrenergic receptors are G protein-coupled receptors for catecholamines that activate the G(i/o) protein pathway, thereby promoting adenylyl cyclase inhibition, ERK1/2 stimulation, and voltage-gated calcium channels suppression.
WDR35	WD repeat-containing protein 35	As a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in ciliogenesis and ciliary protein trafficking.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.3

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
Kinase	2	5.5×	0.193
GPCR	1	2.4×	0.463
Transcription factor	2	1.6×	0.463
Other/Unknown	5	0.9×	0.756

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EVC2	Other/Unknown	no		Limbin, Limbin/EVC
EVC	Other/Unknown	no		Limbin/EVC
DYNC2LI1	Other/Unknown	no		Dynein_light_int_chain, P-loop_NTPase, DYNC2LI1
GLI1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
PRKACA	Kinase	yes	2.7.11.11	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
PRKACB	Kinase	yes	2.7.11.11	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
IFT54	Other/Unknown	no		TRAF3IP1, TRAF3IP1_N, TRAF3IP1_C
CCDC39	Other/Unknown	no		CCDC39
ADRA2C	GPCR	yes		GPCR_Rhodpsn, ADRA2C_rcpt, ADR_fam
WDR35	Transcription factor	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WDR35

Expression context

Cohort genes with no expression data: 0.

8 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	3
sural nerve	2
mucosa of paranasal sinus	2
right uterine tube	2
calcaneal tendon	1
pancreatic ductal cell	1
primordial germ cell in gonad	1
metanephros cortex	1
stromal cell of endometrium	1
olfactory bulb	1
tibial nerve	1
type B pancreatic cell	1
apex of heart	1
gastrocnemius	1
heart left ventricle	1
Brodmann (1909) area 23	1
endothelial cell	1
parietal lobe	1
oocyte	1
endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EVC2	182	ubiquitous	marker	pancreatic ductal cell, calcaneal tendon, primordial germ cell in gonad
EVC	163	ubiquitous	yes	sural nerve, stromal cell of endometrium, metanephros cortex
DYNC2LI1	293	ubiquitous	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus
GLI1	173	broad	yes	tibial nerve, olfactory bulb, type B pancreatic cell
PRKACA	143	ubiquitous	marker	gastrocnemius, apex of heart, heart left ventricle
PRKACB	293	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, parietal lobe
IFT54	265	ubiquitous	marker	oocyte, bronchial epithelial cell, sural nerve
CCDC39	132	tissue_specific	marker	right uterine tube, olfactory segment of nasal mucosa, endometrium
ADRA2C	236	broad	marker	decidua, endocervix, descending thoracic aorta
WDR35	257	ubiquitous	marker	bronchial epithelial cell, mucosa of paranasal sinus, bronchus

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKACA	8,270
PRKACB	7,400
GLI1	4,101
IFT54	1,363
CCDC39	1,218
WDR35	1,032
ADRA2C	1,003
EVC2	913
DYNC2LI1	852
EVC	759

Intra-cohort edges

A	B	Sources
DYNC2LI1	EVC2	string_interaction
DYNC2LI1	WDR35	string_interaction
EVC	EVC2	string_interaction
EVC	WDR35	string_interaction
EVC2	WDR35	string_interaction
PRKACA	PRKACB	intact

Structural data

PDB: 7 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRKACA	P17612	54
GLI1	P08151	5
WDR35	Q9P2L0	4
DYNC2LI1	Q8TCX1	3
IFT54	Q8TDR0	2
CCDC39	Q9UFE4	1
ADRA2C	P18825	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKACB	P22694	95.61
EVC	P57679	74.49
EVC2	Q86UK5	73.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 127. Enrichment computed across 10 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hedgehog ‘off’ state	4	79.3×	1e-05	WDR35, GLI1, PRKACA, PRKACB
PKA-mediated phosphorylation of key metabolic factors	2	507.6×	2e-04	PRKACA, PRKACB
Degradation of GLI1 by the proteasome	3	74.6×	2e-04	GLI1, PRKACA, PRKACB
Regulation of insulin secretion	3	73.2×	2e-04	ADRA2C, PRKACA, PRKACB
HDL assembly	2	317.2×	2e-04	PRKACA, PRKACB
Intraflagellar transport	3	66.8×	2e-04	IFT54, DYNC2LI1, WDR35
Signaling by Hedgehog	3	61.4×	2e-04	EVC2, PRKACA, PRKACB
Integration of energy metabolism	3	58.6×	2e-04	ADRA2C, PRKACA, PRKACB
ROBO receptors bind AKAP5	2	282.0×	3e-04	PRKACA, PRKACB
Hedgehog ‘on’ state	3	52.9×	3e-04	EVC2, EVC, GLI1
Regulation of glycolysis by fructose 2,6-bisphosphate metabolism	2	211.5×	4e-04	PRKACA, PRKACB
CREB1 phosphorylation through the activation of Adenylate Cyclase	2	195.2×	4e-04	PRKACA, PRKACB
Glucose metabolism	2	195.2×	4e-04	PRKACA, PRKACB
Rap1 signalling	2	158.6×	6e-04	PRKACA, PRKACB
Plasma lipoprotein assembly	2	158.6×	6e-04	PRKACA, PRKACB
PKA activation in glucagon signalling	2	149.3×	6e-04	PRKACA, PRKACB
Triglyceride metabolism	2	149.3×	6e-04	PRKACA, PRKACB
PKA activation	2	141.0×	6e-04	PRKACA, PRKACB
Activation of SMO	2	141.0×	6e-04	EVC2, EVC
PKA-mediated phosphorylation of CREB	2	126.9×	7e-04	PRKACA, PRKACB
CD209 (DC-SIGN) signaling	2	115.3×	8e-04	PRKACA, PRKACB
Triglyceride catabolism	2	105.7×	8e-04	PRKACA, PRKACB
DARPP-32 events	2	105.7×	8e-04	PRKACA, PRKACB
Anti-inflammatory response favouring Leishmania parasite infection	2	87.5×	0.001	PRKACA, PRKACB
Leishmania parasite growth and survival	2	87.5×	0.001	PRKACA, PRKACB
Calmodulin induced events	2	84.6×	0.001	PRKACA, PRKACB
CaM pathway	2	84.6×	0.001	PRKACA, PRKACB
Ca-dependent events	2	81.9×	0.001	PRKACA, PRKACB
Aquaporin-mediated transport	2	81.9×	0.001	PRKACA, PRKACB
Glucagon signaling in metabolic regulation	2	76.9×	0.001	PRKACA, PRKACB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dorsal/ventral neural tube patterning	3	240.7×	3e-05	IFT54, PRKACA, PRKACB
negative regulation of smoothened signaling pathway	3	136.6×	8e-05	IFT54, PRKACA, PRKACB
high-density lipoprotein particle assembly	2	337.0×	5e-04	PRKACA, PRKACB
regulation of protein processing	2	306.4×	5e-04	PRKACA, PRKACB
smoothened signaling pathway	3	54.4×	5e-04	EVC2, EVC, GLI1
regulation of osteoblast differentiation	2	259.3×	6e-04	GLI1, PRKACA
intraciliary retrograde transport	2	224.7×	7e-04	DYNC2LI1, WDR35
vascular endothelial cell response to laminar fluid shear stress	2	146.5×	0.001	PRKACA, PRKACB
intraciliary transport	2	112.3×	0.002	IFT54, WDR35
regulation of microtubule cytoskeleton organization	2	108.7×	0.002	IFT54, PRKACA
renal water homeostasis	2	102.1×	0.002	PRKACA, PRKACB
positive regulation of smoothened signaling pathway	2	84.3×	0.003	EVC, GLI1
protein localization to cilium	2	80.2×	0.003	CCDC39, WDR35
negative regulation of TORC1 signaling	2	64.8×	0.004	PRKACA, PRKACB
notochord regression	1	1685.2×	0.006	GLI1
positive regulation of insulin secretion	2	51.1×	0.006	PRKACA, PRKACB
lung development	2	39.6×	0.009	CCDC39, GLI1
regulation of hepatocyte proliferation	1	842.6×	0.009	GLI1
neural tube closure	2	37.5×	0.009	PRKACA, PRKACB
ventral midline development	1	561.7×	0.013	GLI1
morphogenesis of a polarized epithelium	1	421.3×	0.015	IFT54
regulation of cerebellar granule cell precursor proliferation	1	421.3×	0.015	GLI1
protein localization to lipid droplet	1	421.3×	0.015	PRKACA
negative regulation of epinephrine secretion	1	337.0×	0.016	ADRA2C
determination of pancreatic left/right asymmetry	1	337.0×	0.016	CCDC39
adenylate cyclase-inhibiting adrenergic receptor signaling pathway	1	337.0×	0.016	ADRA2C
negative regulation of norepinephrine secretion	1	280.9×	0.016	ADRA2C
cerebellar cortex morphogenesis	1	280.9×	0.016	GLI1
determination of digestive tract left/right asymmetry	1	280.9×	0.016	CCDC39
determination of liver left/right asymmetry	1	280.9×	0.016	CCDC39

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 6

Druggability breadth: 4 of 10 evidence-associated genes (40%) 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
PRKACA	PONATINIB
PRKACB	CAPIVASERTIB
ADRA2C	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADRA2C	330	4
PRKACA	29	4
PRKACB	19	4
GLI1	1	1
EVC2	0	0
EVC	0	0
DYNC2LI1	0	0
IFT54	0	0
CCDC39	0	0
WDR35	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	ADRA2C, PRKACA
BARICITINIB	4	PRKACA
CAPIVASERTIB	4	PRKACA, PRKACB
MIDOSTAURIN	4	PRKACA, PRKACB
DASATINIB	4	ADRA2C, PRKACB
BEPRIDIL	4	ADRA2C
CANDESARTAN CILEXETIL	4	ADRA2C
TELMISARTAN	4	ADRA2C
CLOTRIMAZOLE	4	ADRA2C
SIMVASTATIN	4	ADRA2C
METHYSERGIDE	4	ADRA2C
TIZANIDINE	4	ADRA2C
ACETOPHENAZINE	4	ADRA2C
IMIPRAMINE	4	ADRA2C
DROPERIDOL	4	ADRA2C
RIMONABANT	4	ADRA2C
ALOSETRON	4	ADRA2C
ARIPIPRAZOLE	4	ADRA2C
AMOXAPINE	4	ADRA2C
IDARUBICIN	4	ADRA2C
DESLORATADINE	4	ADRA2C
PRUCALOPRIDE	4	ADRA2C
DULOXETINE	4	ADRA2C
PALONOSETRON	4	ADRA2C
TIOCONAZOLE	4	ADRA2C
NEFAZODONE HYDROCHLORIDE	4	ADRA2C
DESERPIDINE	4	ADRA2C
DIHYDROERGOTAMINE MESYLATE	4	ADRA2C
UNOPROSTONE ISOPROPYL	4	ADRA2C
CINACALCET HYDROCHLORIDE	4	ADRA2C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ADRA2C	647	Binding:503, Functional:135, ADMET:7, Unclassified:2
PRKACA	606	Binding:598, Functional:7, ADMET:1
PRKACB	391	Binding:385, Functional:6
GLI1	44	Binding:44

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKACA	2.7.11.11	cAMP-dependent protein kinase
PRKACB	2.7.11.11	cAMP-dependent protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PRKACA	606
PRKACB	391
ADRA2C	647

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
ADRA2C	1

Chemical tractability of cohort targets

30 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)
PONATINIB	4	ADRA2C, PRKACA
BARICITINIB	4	PRKACA
CAPIVASERTIB	4	PRKACA, PRKACB
MIDOSTAURIN	4	PRKACA, PRKACB
DASATINIB	4	ADRA2C, PRKACB
BEPRIDIL	4	ADRA2C
CANDESARTAN CILEXETIL	4	ADRA2C
TELMISARTAN	4	ADRA2C
CLOTRIMAZOLE	4	ADRA2C
SIMVASTATIN	4	ADRA2C
METHYSERGIDE	4	ADRA2C
TIZANIDINE	4	ADRA2C
ACETOPHENAZINE	4	ADRA2C
IMIPRAMINE	4	ADRA2C
DROPERIDOL	4	ADRA2C
RIMONABANT	4	ADRA2C
ALOSETRON	4	ADRA2C
ARIPIPRAZOLE	4	ADRA2C
AMOXAPINE	4	ADRA2C
IDARUBICIN	4	ADRA2C
DESLORATADINE	4	ADRA2C
PRUCALOPRIDE	4	ADRA2C
DULOXETINE	4	ADRA2C
PALONOSETRON	4	ADRA2C
TIOCONAZOLE	4	ADRA2C
NEFAZODONE HYDROCHLORIDE	4	ADRA2C
DESERPIDINE	4	ADRA2C
DIHYDROERGOTAMINE MESYLATE	4	ADRA2C
UNOPROSTONE ISOPROPYL	4	ADRA2C
CINACALCET HYDROCHLORIDE	4	ADRA2C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	PRKACA, PRKACB, ADRA2C
B	Phased (≥1) drug, not yet approved	1	GLI1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	EVC2, EVC, DYNC2LI1, IFT54, CCDC39, WDR35

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EVC2	0	—
EVC	0	—
DYNC2LI1	0	—
IFT54	0	—
CCDC39	0	—
WDR35	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.