Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Summary

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (MONDO:0008278) is a disease caused by SMAD4 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SMAD4 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 915

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Mondo ID	MONDO:0008278
MeSH	C563412
OMIM	175050
DOID	DOID:0111543
UMLS	C1832942
MedGen	331400
GARD	0024614
Is cancer (heuristic)	no

Also known as: JPHT · juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome · polyposis, generalised juvenile, with pulmonary arteriovenous malformation · SMAD4-related juvenile polyposis/hemorrhagic telangiectasia syndrome

Data availability: 915 ClinVar variants · 4 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 › juvenile polyposis/hereditary hemorrhagic telangiectasia 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, 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, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, 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:

186 benign/likely benign, 124 uncertain significance, 80 likely benign, 77 conflicting classifications of pathogenicity, 76 benign, 33 pathogenic, 14 likely pathogenic, 9 pathogenic/likely pathogenic, 1 benign; confers sensitivity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3892514	NC_000015.10:g.48310852_48310879dup	DUT-AS1	Pathogenic	criteria provided, single submitter
127949	NM_005359.6(SMAD4):c.1351_1375del (p.Ala451fs)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1372436	NM_005359.6(SMAD4):c.1523del (p.Gly508fs)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142253	NM_005359.6(SMAD4):c.1245_1248del (p.Asp415Glufs)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
1756201	NM_005359.6(SMAD4):c.692del (p.Gly231fs)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
1774939	NM_005359.6(SMAD4):c.1546C>T (p.Gln516Ter)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
182867	NM_005359.6(SMAD4):c.1231_1232del (p.Ser411fs)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
233900	NM_005359.6(SMAD4):c.1349_1376dup (p.Ala460fs)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
240143	NM_005359.6(SMAD4):c.1206dup (p.Ser403Ter)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
2431265	NM_005359.6(SMAD4):c.1552dup (p.Ile518fs)	SMAD4	Pathogenic	criteria provided, single submitter
2431333	NM_005359.6(SMAD4):c.513_514del (p.Leu172fs)	SMAD4	Pathogenic	criteria provided, single submitter
24802	NM_005359.6(SMAD4):c.403C>T (p.Arg135Ter)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
24804	NM_005359.6(SMAD4):c.430_431del (p.Ser144fs)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
24807	NM_005359.6(SMAD4):c.533C>G (p.Ser178Ter)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
24811	NM_005359.6(SMAD4):c.692dup (p.Ser232fs)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
24813	NM_005359.5(SMAD4):c.731_732insGCCC(p.Gln245Profs)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
24827	NM_005359.6(SMAD4):c.1054G>A (p.Gly352Arg)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
24830	NM_005359.6(SMAD4):c.1081C>G (p.Arg361Gly)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
24832	NM_005359.6(SMAD4):c.1082G>A (p.Arg361His)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
24850	NM_005359.6(SMAD4):c.1333C>T (p.Arg445Ter)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
24871	NM_005359.6(SMAD4):c.1596_1597delinsT (p.Leu533fs)	SMAD4	Pathogenic	no assertion criteria provided
24878	NM_005359.6(SMAD4):c.1612_1625del (p.Glu538fs)	SMAD4	Pathogenic	no assertion criteria provided
2626886	NM_005359.6(SMAD4):c.875del (p.Pro292fs)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674425	NM_005359.6(SMAD4):c.699dup (p.Ser234Ter)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
30150	NM_005359.6(SMAD4):c.1498A>G (p.Ile500Val)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
3148020	NM_005359.6(SMAD4):c.593del (p.Pro198fs)	SMAD4	Pathogenic	criteria provided, single submitter
3148342	NM_005359.6(SMAD4):c.1355del (p.Ala452fs)	SMAD4	Pathogenic	criteria provided, single submitter
3148389	NM_005359.6(SMAD4):c.586dup (p.Ser196fs)	SMAD4	Pathogenic	criteria provided, single submitter
3148459	NC_000018.10:g.51076638del	SMAD4	Pathogenic	criteria provided, single submitter
3148572	NM_005359.6(SMAD4):c.803_804insCTAAGTGGTAGTAG (p.Trp268delinsCysTer)	SMAD4	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 5 · 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
SMAD4	Definitive	Autosomal dominant	juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMAD4	Orphanet:1333	Familial pancreatic carcinoma
SMAD4	Orphanet:2588	Myhre syndrome
SMAD4	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
SMAD4	Orphanet:774	Hereditary hemorrhagic telangiectasia
SMAD4	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	gencc,clinvar
OR10Z1	HGNC:14996	ENSG00000198967	Q8NGY1	Olfactory receptor 10Z1	clinvar
DUT-AS1	HGNC:55420	ENSG00000259488		DUT antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.
OR10Z1	Olfactory receptor 10Z1	Odorant receptor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
GPCR	1	8.0×	0.240
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
OR10Z1	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
DUT-AS1	Other/Unknown	no

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
bone marrow cell	2
calcaneal tendon	1
ganglionic eminence	1
ventricular zone	1
bone marrow	1
male germ line stem cell (sensu Vertebrata) in testis	1
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
OR10Z1	36		marker	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, bone marrow cell
DUT-AS1	132		marker	sural nerve, colonic epithelium, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD4	7,320
OR10Z1	132
DUT-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMAD4	Q13485	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OR10Z1	Q8NGY1	85.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. 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
Loss of Function of SMAD4 in Cancer	1	1903.3×	0.009	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	1903.3×	0.009	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	1903.3×	0.009	SMAD4
RUNX3 regulates BCL2L11 (BIM) transcription	1	1142.0×	0.009	SMAD4
Loss of Function of SMAD2/3 in Cancer	1	951.7×	0.009	SMAD4
Signaling by TGF-beta Receptor Complex in Cancer	1	951.7×	0.009	SMAD4
RUNX3 regulates CDKN1A transcription	1	815.7×	0.009	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation	1	571.0×	0.011	SMAD4
RUNX2 regulates bone development	1	407.9×	0.011	SMAD4
Signaling by Activin	1	380.7×	0.011	SMAD4
Formation of definitive endoderm	1	356.9×	0.011	SMAD4
FOXO-mediated transcription of cell cycle genes	1	335.9×	0.011	SMAD4
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	335.9×	0.011	SMAD4
Germ layer formation at gastrulation	1	335.9×	0.011	SMAD4
Transcriptional regulation of pluripotent stem cells	1	271.9×	0.012	SMAD4
Signaling by NODAL	1	248.3×	0.012	SMAD4
TGFBR3 expression	1	228.4×	0.012	SMAD4
Cardiogenesis	1	211.5×	0.012	SMAD4
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	190.3×	0.012	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	190.3×	0.012	SMAD4
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	184.2×	0.012	SMAD4
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	184.2×	0.012	SMAD4
Signaling by TGFBR3	1	184.2×	0.012	SMAD4
Signaling by BMP	1	178.4×	0.012	SMAD4
FOXO-mediated transcription	1	167.9×	0.012	SMAD4
TGF-beta receptor signaling activates SMADs	1	163.1×	0.012	SMAD4
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	154.3×	0.012	SMAD4
Transcriptional regulation by RUNX3	1	135.9×	0.013	SMAD4
Gastrulation	1	129.8×	0.013	SMAD4
Transcriptional regulation by RUNX2	1	126.9×	0.013	SMAD4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete positive regulation of cell proliferation involved in heart valve morphogenesis	1	8426.0×	0.003	SMAD4
female gonad morphogenesis	1	8426.0×	0.003	SMAD4
negative regulation of cardiac myofibril assembly	1	8426.0×	0.003	SMAD4
nephrogenic mesenchyme morphogenesis	1	4213.0×	0.004	SMAD4
metanephric mesenchyme morphogenesis	1	2808.7×	0.004	SMAD4
atrioventricular valve formation	1	2106.5×	0.004	SMAD4
left ventricular cardiac muscle tissue morphogenesis	1	2106.5×	0.004	SMAD4
regulation of transforming growth factor beta2 production	1	2106.5×	0.004	SMAD4
formation of anatomical boundary	1	2106.5×	0.004	SMAD4
regulation of hair follicle development	1	2106.5×	0.004	SMAD4
positive regulation of luteinizing hormone secretion	1	1685.2×	0.004	SMAD4
positive regulation of follicle-stimulating hormone secretion	1	1404.3×	0.004	SMAD4
endocardial cell differentiation	1	1404.3×	0.004	SMAD4
brainstem development	1	1053.2×	0.005	SMAD4
sebaceous gland development	1	1053.2×	0.005	SMAD4
mesendoderm development	1	936.2×	0.005	SMAD4
response to transforming growth factor beta	1	936.2×	0.005	SMAD4
positive regulation of extracellular matrix assembly	1	936.2×	0.005	SMAD4
endothelial cell activation	1	842.6×	0.005	SMAD4
neural crest cell differentiation	1	766.0×	0.005	SMAD4
somite rostral/caudal axis specification	1	766.0×	0.005	SMAD4
atrioventricular canal development	1	766.0×	0.005	SMAD4
epithelial to mesenchymal transition involved in endocardial cushion formation	1	702.2×	0.005	SMAD4
positive regulation of cardiac muscle cell apoptotic process	1	601.9×	0.005	SMAD4
secondary palate development	1	601.9×	0.005	SMAD4
negative regulation of cardiac muscle hypertrophy	1	561.7×	0.005	SMAD4
interleukin-6-mediated signaling pathway	1	561.7×	0.005	SMAD4
cardiac conduction system development	1	526.6×	0.005	SMAD4
cardiac muscle hypertrophy in response to stress	1	526.6×	0.005	SMAD4
gastrulation with mouth forming second	1	468.1×	0.006	SMAD4

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMAD4	0	0
OR10Z1	0	0
DUT-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMAD4	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	OR10Z1
E	Difficult family or no structure, no drug	2	SMAD4, DUT-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMAD4	6	—
OR10Z1	0	—
DUT-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.