Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

Summary

Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (MONDO:0014369) is a disease caused by GLI2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GLI2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 664

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		112	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
Mondo ID	MONDO:0014369
OMIM	615849
Orphanet	420584
DOID	DOID:0080328
UMLS	C4014479
MedGen	862916
GARD	0013349
Is cancer (heuristic)	no

Also known as: CJS · Culler-Jones syndrome · Pallister-Hall syndrome 2

Data availability: 664 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid 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

600 retrieved; paginated sample, class counts are floors:

272 uncertain significance, 178 likely benign, 56 conflicting classifications of pathogenicity, 33 benign/likely benign, 25 benign, 20 pathogenic, 14 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1285585	NM_001374353.1(GLI2):c.2283del (p.Ala763fs)	GLI2	Pathogenic	criteria provided, single submitter
1371947	NM_001374353.1(GLI2):c.49del (p.Ser17fs)	GLI2	Pathogenic	criteria provided, single submitter
139428	GLI2, 1256TER	GLI2	Pathogenic	no assertion criteria provided
139429	NM_001374353.1(GLI2):c.2311_2317del (p.Leu771fs)	GLI2	Pathogenic	no assertion criteria provided
139430	NM_001374353.1(GLI2):c.2030_2033del (p.Leu677fs)	GLI2	Pathogenic	no assertion criteria provided
139431	NM_001374353.1(GLI2):c.1138G>T (p.Glu380Ter)	GLI2	Pathogenic	no assertion criteria provided
2006699	NM_001374353.1(GLI2):c.4311C>G (p.Tyr1437Ter)	GLI2	Pathogenic	criteria provided, single submitter
2034980	NM_001374353.1(GLI2):c.1393A>T (p.Lys465Ter)	GLI2	Pathogenic	criteria provided, single submitter
2112984	NM_001374353.1(GLI2):c.9dup (p.Ser4fs)	GLI2	Pathogenic	criteria provided, single submitter
235076	NM_001374353.1(GLI2):c.790C>T (p.Arg264Ter)	GLI2	Pathogenic	criteria provided, multiple submitters, no conflicts
2429354	NM_001374353.1(GLI2):c.2302_2306dup (p.Arg770fs)	GLI2	Pathogenic	criteria provided, single submitter
2441742	NM_001374353.1(GLI2):c.2454del (p.Ser819fs)	GLI2	Pathogenic	criteria provided, single submitter
2582463	NM_001374353.1(GLI2):c.2509_2510del (p.Ser837fs)	GLI2	Pathogenic	criteria provided, single submitter
2628336	NM_001374353.1(GLI2):c.3523C>T (p.Gln1175Ter)	GLI2	Pathogenic	criteria provided, single submitter
2932634	NM_001374353.1(GLI2):c.1934C>A (p.Ser645Ter)	GLI2	Pathogenic	criteria provided, single submitter
2951021	NM_001374353.1(GLI2):c.2651del (p.Pro884fs)	GLI2	Pathogenic	criteria provided, single submitter
4056448	NM_001374353.1(GLI2):c.1473_1510dup (p.Lys504delinsArgAlaAlaArgArgProThrProAlaTrpArgThrTer)	GLI2	Pathogenic	criteria provided, single submitter
4787294	NM_001374353.1(GLI2):c.904C>T (p.Gln302Ter)	GLI2	Pathogenic	criteria provided, single submitter
498545	NM_001374353.1(GLI2):c.1370G>A (p.Trp457Ter)	GLI2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522404	NM_001374353.1(GLI2):c.2263del (p.Ser755fs)	GLI2	Pathogenic	no assertion criteria provided
573009	NM_001374353.1(GLI2):c.192dup (p.Asp65Ter)	GLI2	Pathogenic	criteria provided, multiple submitters, no conflicts
576501	NM_001374353.1(GLI2):c.1905+1G>A	GLI2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172578	NM_001374353.1(GLI2):c.900del (p.Ser301fs)	GLI2	Likely pathogenic	criteria provided, single submitter
1802570	NM_001374353.1(GLI2):c.4426_4428del (p.Val1476del)	GLI2	Likely pathogenic	criteria provided, single submitter
2579153	NM_001374353.1(GLI2):c.1183-45del	GLI2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2947133	NM_001374353.1(GLI2):c.149-877_238del	GLI2	Likely pathogenic	criteria provided, single submitter
3068372	NM_001374353.1(GLI2):c.1427A>G (p.His476Arg)	GLI2	Likely pathogenic	criteria provided, single submitter
3236584	NM_001374353.1(GLI2):c.254+1G>T	GLI2	Likely pathogenic	criteria provided, single submitter
3382280	NM_001374353.1(GLI2):c.693_696dup (p.Leu233fs)	GLI2	Likely pathogenic	criteria provided, single submitter
3382439	NM_001374353.1(GLI2):c.349del (p.Ala117fs)	GLI2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 12 · 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
GLI2	Definitive	Autosomal dominant	postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLI2	Orphanet:220386	Semilobar holoprosencephaly
GLI2	Orphanet:280195	Septopreoptic holoprosencephaly
GLI2	Orphanet:280200	Microform holoprosencephaly
GLI2	Orphanet:420584	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
GLI2	Orphanet:93924	Lobar holoprosencephaly
GLI2	Orphanet:93925	Alobar holoprosencephaly
GLI2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
HOXA2	Orphanet:140963	Bilateral microtia-deafness-cleft palate syndrome
HOXA2	Orphanet:83463	Microtia
PDE4D	Orphanet:439822	PDE4D haploinsufficiency syndrome
PDE4D	Orphanet:950	Acrodysostosis

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
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	gencc,clinvar
HOXA2	HGNC:5103	ENSG00000105996	O43364	Homeobox protein Hox-A2	clinvar
PDE4D	HGNC:8783	ENSG00000113448	Q08499	3’,5’-cyclic-AMP phosphodiesterase 4D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.
HOXA2	Homeobox protein Hox-A2	Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
PDE4D	3’,5’-cyclic-AMP phosphodiesterase 4D	Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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
Transcription factor	2	5.5×	0.081
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
HOXA2	Transcription factor	no		HD, Homeobox_Antennapedia_CS, Homeodomain-like_sf
PDE4D	Enzyme (other)	yes	3.1.4.53	PDEase_catalytic_dom, PDEase, PDEase_CS

Expression context

Cohort genes with no expression data: 0.

2 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
germinal epithelium of ovary	1
tibia	1
ventricular zone	1
buccal mucosa cell	1
descending thoracic aorta	1
mucosa of transverse colon	1
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone
HOXA2	133	broad	yes	buccal mucosa cell, mucosa of transverse colon, descending thoracic aorta
PDE4D	283	ubiquitous	marker	gluteal muscle, biceps brachii, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI2	3,112
PDE4D	1,533
HOXA2	1,256

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE4D	Q08499	122

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HOXA2	O43364	58.47
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX2 regulates chondrocyte maturation	1	761.3×	0.009	GLI2
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	543.8×	0.009	GLI2
DARPP-32 events	1	158.6×	0.021	PDE4D
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.021	PDE4D
Degradation of GLI2 by the proteasome	1	74.6×	0.027	GLI2
Hedgehog ‘off’ state	1	59.5×	0.027	GLI2
Hedgehog ‘on’ state	1	52.9×	0.027	GLI2
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	30.4×	0.041	HOXA2
G alpha (s) signalling events	1	24.4×	0.043	PDE4D
Regulation of expression of SLITs and ROBOs	1	23.1×	0.043	HOXA2

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
osteoblast development	2	660.9×	2e-04	GLI2, HOXA2
rhombomere 3 morphogenesis	1	5617.3×	0.005	HOXA2
rhombomere 2 development	1	2808.7×	0.005	HOXA2
negative regulation of relaxation of cardiac muscle	1	2808.7×	0.005	PDE4D
ventral midline development	1	1872.4×	0.005	GLI2
floor plate formation	1	1872.4×	0.005	GLI2
spinal cord ventral commissure morphogenesis	1	1872.4×	0.005	GLI2
brain segmentation	1	1872.4×	0.005	HOXA2
hindgut morphogenesis	1	1404.3×	0.005	GLI2
tube development	1	1404.3×	0.005	GLI2
negative regulation of heart contraction	1	1404.3×	0.005	PDE4D
cerebellar cortex morphogenesis	1	936.2×	0.006	GLI2
segment specification	1	702.2×	0.006	HOXA2
spinal cord dorsal/ventral patterning	1	702.2×	0.006	GLI2
cAMP catabolic process	1	624.1×	0.006	PDE4D
ventral spinal cord development	1	624.1×	0.006	GLI2
adrenergic receptor signaling pathway	1	624.1×	0.006	PDE4D
regulation of cell communication by electrical coupling involved in cardiac conduction	1	624.1×	0.006	PDE4D
epidermal cell differentiation	1	561.7×	0.006	GLI2
embryonic viscerocranium morphogenesis	1	561.7×	0.006	HOXA2
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	561.7×	0.006	PDE4D
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	561.7×	0.006	PDE4D
positive regulation of T cell differentiation in thymus	1	510.7×	0.006	GLI2
positive regulation of interleukin-5 production	1	468.1×	0.006	PDE4D
muscle structure development	1	468.1×	0.006	HOXA2
cellular response to epinephrine stimulus	1	432.1×	0.006	PDE4D
hindbrain development	1	374.5×	0.007	GLI2
regulation of cardiac muscle cell contraction	1	374.5×	0.007	PDE4D
embryonic digestive tract development	1	330.4×	0.007	GLI2
cell fate determination	1	312.1×	0.007	HOXA2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
PDE4D	INAMRINONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE4D	269	4
GLI2	0	0
HOXA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INAMRINONE	4	PDE4D
THEOPHYLLINE	4	PDE4D
VARDENAFIL	4	PDE4D
MILRINONE	4	PDE4D
LOSARTAN	4	PDE4D
SILDENAFIL	4	PDE4D
ROFLUMILAST	4	PDE4D
ENOXIMONE	4	PDE4D
ENSIFENTRINE	4	PDE4D
CRISABOROLE	4	PDE4D
APREMILAST	4	PDE4D
PENTOXIFYLLINE	4	PDE4D
TADALAFIL	4	PDE4D
DIPYRIDAMOLE	4	PDE4D
CANDESARTAN CILEXETIL	4	PDE4D
TELMISARTAN	4	PDE4D
SIMVASTATIN	4	PDE4D
MORICIZINE	4	PDE4D
AMLEXANOX	4	PDE4D
AMOXAPINE	4	PDE4D
PONATINIB	4	PDE4D
RUCAPARIB	4	PDE4D
CELECOXIB	4	PDE4D
VILANTEROL	4	PDE4D
TIOCONAZOLE	4	PDE4D
UNOPROSTONE ISOPROPYL	4	PDE4D
OLMESARTAN MEDOXOMIL	4	PDE4D
HYDROXYPROGESTERONE CAPROATE	4	PDE4D
NORGESTIMATE	4	PDE4D
THIOTHIXENE	4	PDE4D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PDE4D	863	Binding:805, Functional:33, ADMET:23, Toxicity:2
GLI2	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDE4D	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PDE4D	863

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

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)
INAMRINONE	4	PDE4D
THEOPHYLLINE	4	PDE4D
VARDENAFIL	4	PDE4D
MILRINONE	4	PDE4D
LOSARTAN	4	PDE4D
SILDENAFIL	4	PDE4D
ROFLUMILAST	4	PDE4D
ENOXIMONE	4	PDE4D
ENSIFENTRINE	4	PDE4D
CRISABOROLE	4	PDE4D
APREMILAST	4	PDE4D
PENTOXIFYLLINE	4	PDE4D
TADALAFIL	4	PDE4D
DIPYRIDAMOLE	4	PDE4D
CANDESARTAN CILEXETIL	4	PDE4D
TELMISARTAN	4	PDE4D
SIMVASTATIN	4	PDE4D
MORICIZINE	4	PDE4D
AMLEXANOX	4	PDE4D
AMOXAPINE	4	PDE4D
PONATINIB	4	PDE4D
RUCAPARIB	4	PDE4D
CELECOXIB	4	PDE4D
VILANTEROL	4	PDE4D
TIOCONAZOLE	4	PDE4D
UNOPROSTONE ISOPROPYL	4	PDE4D
OLMESARTAN MEDOXOMIL	4	PDE4D
HYDROXYPROGESTERONE CAPROATE	4	PDE4D
NORGESTIMATE	4	PDE4D
THIOTHIXENE	4	PDE4D

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDE4D
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	GLI2, HOXA2

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)
GLI2	6	—
HOXA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.