Generalized juvenile polyposis/juvenile polyposis coli

Summary

Generalized juvenile polyposis/juvenile polyposis coli (MONDO:0008276) is a disease caused by variants in BMPR1A and SMAD4, with 6 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: BMPR1A (GenCC Definitive), SMAD4 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 349
• Phenotypes (HPO): 11
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002573	Hematochezia	Frequent (30-79%)
HP:0001017	Anemic pallor	Frequent (30-79%)
HP:0005227	Adenomatous colonic polyposis	Frequent (30-79%)
HP:0100896	Rectal polyposis	Frequent (30-79%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0004394	Multiple gastric polyps	Occasional (5-29%)
HP:0030256	Small intestinal polyposis	Very rare (<1-4%)
HP:0004783	Duodenal polyposis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	generalized juvenile polyposis/juvenile polyposis coli
Mondo ID	MONDO:0008276
Orphanet	329971
DOID	DOID:0050787
UMLS	C1868081
MedGen	356898
GARD	0017508
Is cancer (heuristic)	no

Also known as: generalized juvenile polyposis/juvenile polyposis coli · jPS · juvenile polyposis syndrome

Data availability: 349 ClinVar variants · 5 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 › generalized juvenile polyposis/juvenile polyposis coli

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, 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, 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

349 retrieved; paginated sample, class counts are floors:

156 uncertain significance, 65 conflicting classifications of pathogenicity, 44 pathogenic, 35 benign, 26 benign/likely benign, 11 likely pathogenic, 8 pathogenic/likely pathogenic, 3 likely benign, 1 benign; confers sensitivity

ClinVar	Variant (HGVS)	Gene	Classification	Review
559459	Single allele		Pathogenic	criteria provided, single submitter
583733	NC_000010.10:g.(?88649809)(89725239_?)del	ADIRF	Pathogenic	criteria provided, single submitter
831623	NC_000010.11:g.(?86755016)(87965564_?)del	ADIRF-AS1	Pathogenic	criteria provided, single submitter
142484	NM_004329.3(BMPR1A):c.355C>T (p.Arg119Cys)	BMPR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142735	NM_004329.3(BMPR1A):c.682C>T (p.Arg228Ter)	BMPR1A	Pathogenic	criteria provided, multiple submitters, no conflicts
183728	NM_004329.3(BMPR1A):c.1081C>T (p.Arg361Ter)	BMPR1A	Pathogenic	criteria provided, multiple submitters, no conflicts
188270	NM_004329.3(BMPR1A):c.247_251del (p.Phe83fs)	BMPR1A	Pathogenic	criteria provided, multiple submitters, no conflicts
239852	NM_004329.2(BMPR1A):c.-152-?_*1469del	BMPR1A	Pathogenic	criteria provided, single submitter
239867	NM_004329.3(BMPR1A):c.771del (p.Val258fs)	BMPR1A	Pathogenic	criteria provided, single submitter
4056170	NM_004329.3(BMPR1A):c.703C>T (p.Gln235Ter)	BMPR1A	Pathogenic	criteria provided, single submitter
417562	NC_000010.11:g.(?86838865)(86900126_?)del	BMPR1A	Pathogenic	criteria provided, single submitter
429103	NM_004329.3(BMPR1A):c.1221C>G (p.Tyr407Ter)	BMPR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
529908	NM_004329.3(BMPR1A):c.44_47del (p.Leu15fs)	BMPR1A	Pathogenic	criteria provided, multiple submitters, no conflicts
529927	NM_004329.3(BMPR1A):c.366_384del (p.Glu123fs)	BMPR1A	Pathogenic	criteria provided, single submitter
571700	NM_004329.3(BMPR1A):c.-547_-268+1del	BMPR1A	Pathogenic	criteria provided, single submitter
584294	NC_000010.11:g.(?86912230)(86917336_?)del	BMPR1A	Pathogenic	criteria provided, single submitter
617784	NM_004329.3(BMPR1A):c.176T>A (p.Leu59Ter)	BMPR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
644109	NM_004329.3(BMPR1A):c.150del (p.Ala51fs)	BMPR1A	Pathogenic	criteria provided, single submitter
644978	NM_004329.3(BMPR1A):c.110_111insCCATGGCACTGGGAT (p.Ser37_Asp38insHisGlyThrGlyIle)	BMPR1A	Pathogenic	criteria provided, single submitter
649055	NC_000010.11:g.(?86876009)(86923729_?)del	BMPR1A	Pathogenic	criteria provided, single submitter
660680	NC_000010.11:g.(?86876009)(86876095_?)del	BMPR1A	Pathogenic	criteria provided, single submitter
802600	NM_004329.3(BMPR1A):c.583C>T (p.Gln195Ter)	BMPR1A	Pathogenic	criteria provided, multiple submitters, no conflicts
832499	NC_000010.11:g.(?86755016)(86923719_?)del	BMPR1A	Pathogenic	criteria provided, single submitter
832863	NC_000010.11:g.(?86875868)(86876095_?)del	BMPR1A	Pathogenic	criteria provided, single submitter
832888	NC_000010.11:g.(?86668692)(86954160_?)del	BMPR1A	Pathogenic	criteria provided, single submitter
978679	NM_004329.3(BMPR1A):c.1114A>T (p.Lys372Ter)	BMPR1A	Pathogenic	criteria provided, single submitter
981981	NC_000010.11:g.(86838980_86875866)_(86876086_86890061)del	BMPR1A	Pathogenic	criteria provided, single submitter
646972	NC_000010.11:g.(?86838866)(87965482_?)del	KLLN	Pathogenic	criteria provided, single submitter
661198	NC_000010.11:g.(?86755016)(87965482_?)del	LOC121366071	Pathogenic	criteria provided, single submitter
1050750	NM_000455.5(STK11):c.-2_290+1013del	LOC125371447	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · 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
BMPR1A	Definitive	Autosomal dominant	generalized juvenile polyposis/juvenile polyposis coli	12
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
BMPR1A	Orphanet:157794	Hereditary mixed polyposis syndrome
BMPR1A	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
BMPR1A	Orphanet:440437	Familial colorectal cancer Type X
BMPR1A	Orphanet:79076	Juvenile polyposis of infancy
STK11	Orphanet:2869	Peutz-Jeghers syndrome
KLLN	Orphanet:201	Cowden syndrome
KLLN	Orphanet:227535	Hereditary breast cancer

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	gencc,clinvar,civic_evidence
BMPR1A	HGNC:1076	ENSG00000107779	P36894	Bone morphogenetic protein receptor type-1A	gencc,clinvar
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	clinvar
ADIRF	HGNC:24043	ENSG00000148671	Q15847	Adipogenesis regulatory factor	clinvar
KLLN	HGNC:37212	ENSG00000227268	B2CW77	Killin	clinvar
ADIRF-AS1	HGNC:45127	ENSG00000272734		ADIRF 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.
BMPR1A	Bone morphogenetic protein receptor type-1A	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…
ADIRF	Adipogenesis regulatory factor	Plays a role in fat cell development; promotes adipogenic differentiation and stimulates transcription initiation of master adipogenesis factors like PPARG and CEBPA at early stages of preadipocyte differentiation.
KLLN	Killin	DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · 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
Kinase	2	9.2×	0.035
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
BMPR1A	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ADIRF	Other/Unknown	no		ADIRF
KLLN	Other/Unknown	no
ADIRF-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
left testis	2
ganglionic eminence	1
ventricular zone	1
saphenous vein	1
secondary oocyte	1
hindlimb stylopod muscle	1
right testis	1
left coronary artery	1
popliteal artery	1
tibial artery	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1
tibialis anterior	1
skin of abdomen	1
skin of leg	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
BMPR1A	284	ubiquitous	marker	secondary oocyte, calcaneal tendon, saphenous vein
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
ADIRF	280	ubiquitous	marker	popliteal artery, tibial artery, left coronary artery
KLLN	149		marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
ADIRF-AS1	170	ubiquitous	marker	skin of leg, skin of abdomen, left testis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD4	7,320
STK11	5,146
BMPR1A	3,316
ADIRF	594
KLLN	234
ADIRF-AS1	0

Intra-cohort edges

A	B	Sources
BMPR1A	SMAD4	string_interaction
SMAD4	STK11	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMAD4	Q13485	12
BMPR1A	P36894	11
STK11	Q15831	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADIRF	Q15847	74.15
KLLN	B2CW77	51.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 59. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by BMP	2	178.4×	0.002	SMAD4, BMPR1A
FOXO-mediated transcription	2	167.9×	0.002	SMAD4, STK11
Adipogenesis	2	78.2×	0.005	SMAD4, ADIRF
Signaling by TGFB family members	2	57.7×	0.007	SMAD4, BMPR1A
Loss of Function of SMAD4 in Cancer	1	951.7×	0.009	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	951.7×	0.009	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	951.7×	0.009	SMAD4
RUNX3 regulates BCL2L11 (BIM) transcription	1	571.0×	0.012	SMAD4
Loss of Function of SMAD2/3 in Cancer	1	475.8×	0.012	SMAD4
Signaling by TGF-beta Receptor Complex in Cancer	1	475.8×	0.012	SMAD4
RUNX3 regulates CDKN1A transcription	1	407.9×	0.013	SMAD4
AMPK inhibits chREBP transcriptional activation activity	1	356.9×	0.014	STK11
Transcriptional regulation of brown and beige adipocyte differentiation	1	285.5×	0.015	SMAD4
Signal Transduction	3	7.6×	0.015	SMAD4, BMPR1A, STK11
RUNX2 regulates bone development	1	203.9×	0.017	SMAD4
Signaling by Activin	1	190.3×	0.017	SMAD4
FOXO-mediated transcription of cell death genes	1	178.4×	0.017	STK11
Formation of definitive endoderm	1	178.4×	0.017	SMAD4
FOXO-mediated transcription of cell cycle genes	1	167.9×	0.017	SMAD4
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	167.9×	0.017	SMAD4
Germ layer formation at gastrulation	1	167.9×	0.017	SMAD4
Transcriptional regulation of pluripotent stem cells	1	135.9×	0.020	SMAD4
Signaling by NODAL	1	124.1×	0.021	SMAD4
TGFBR3 expression	1	114.2×	0.021	SMAD4
Cardiogenesis	1	105.7×	0.021	SMAD4
Energy dependent regulation of mTOR by LKB1-AMPK	1	98.5×	0.021	STK11
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	95.2×	0.021	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	95.2×	0.021	SMAD4
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	92.1×	0.021	SMAD4
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	92.1×	0.021	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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mesendoderm development	2	749.0×	4e-04	SMAD4, BMPR1A
cardiac conduction system development	2	421.3×	7e-04	SMAD4, BMPR1A
developmental growth	2	293.1×	0.001	SMAD4, BMPR1A
outflow tract septum morphogenesis	2	259.3×	0.001	SMAD4, BMPR1A
cellular response to BMP stimulus	2	224.7×	0.001	SMAD4, BMPR1A
positive regulation of transforming growth factor beta receptor signaling pathway	2	210.7×	0.001	SMAD4, STK11
ventricular septum morphogenesis	2	172.8×	0.001	SMAD4, BMPR1A
positive regulation of SMAD protein signal transduction	2	153.2×	0.001	SMAD4, BMPR1A
embryonic digit morphogenesis	2	120.4×	0.002	SMAD4, BMPR1A
positive regulation of miRNA transcription	2	116.2×	0.002	SMAD4, BMPR1A
obsolete positive regulation of cell proliferation involved in heart valve morphogenesis	1	3370.4×	0.003	SMAD4
neural plate mediolateral regionalization	1	3370.4×	0.003	BMPR1A
paraxial mesoderm structural organization	1	3370.4×	0.003	BMPR1A
female gonad morphogenesis	1	3370.4×	0.003	SMAD4
positive regulation of vesicle transport along microtubule	1	3370.4×	0.003	STK11
positive regulation of cardiac ventricle development	1	3370.4×	0.003	BMPR1A
fibrous ring of heart morphogenesis	1	3370.4×	0.003	BMPR1A
negative regulation of cardiac myofibril assembly	1	3370.4×	0.003	SMAD4
BMP signaling pathway	2	80.2×	0.003	SMAD4, BMPR1A
transforming growth factor beta receptor signaling pathway	2	63.6×	0.003	SMAD4, BMPR1A
cell differentiation	3	17.5×	0.003	SMAD4, BMPR1A, ADIRF
negative regulation of cell growth	2	57.6×	0.004	SMAD4, STK11
nephrogenic mesenchyme morphogenesis	1	1685.2×	0.005	SMAD4
osteoblast differentiation	2	48.5×	0.005	SMAD4, BMPR1A
negative regulation of canonical Wnt signaling pathway	2	47.1×	0.005	SMAD4, STK11
positive regulation of transforming growth factor beta2 production	1	1123.5×	0.006	BMPR1A
regulation of lateral mesodermal cell fate specification	1	1123.5×	0.006	BMPR1A
metanephric mesenchyme morphogenesis	1	1123.5×	0.006	SMAD4
atrioventricular valve development	1	842.6×	0.006	BMPR1A
atrioventricular valve formation	1	842.6×	0.006	SMAD4

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) 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
BMPR1A	MOMELOTINIB
STK11	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STK11	17	4
BMPR1A	11	4
SMAD4	0	0
ADIRF	0	0
KLLN	0	0
ADIRF-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	BMPR1A
GILTERITINIB	4	BMPR1A
DASATINIB	4	BMPR1A
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	STK11
SUNITINIB	4	STK11
MIDOSTAURIN	4	STK11
SARACATINIB	3	BMPR1A
LESTAURTINIB	3	BMPR1A, STK11
DINACICLIB	3	STK11
DOVITINIB	3	STK11
RUBOXISTAURIN	3	STK11
AT-9283	2	BMPR1A
ZILURGISERTIB	2	BMPR1A
KER-047	2	BMPR1A
AZD-1480	2	STK11
SU-014813	2	STK11
R-406	2	STK11
TOZASERTIB	2	STK11
KW-2449	1	BMPR1A, STK11
XL-228	1	BMPR1A, STK11
Y-39983	1	BMPR1A
PF-00562271	1	STK11
PF-03758309	1	STK11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
STK11	244	Binding:244
BMPR1A	169	Binding:166, ADMET:3
SMAD4	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BMPR1A	2.7.10.2	non-specific protein-tyrosine kinase
STK11	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BMPR1A	169
STK11	244

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

25 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)
MOMELOTINIB	4	BMPR1A
GILTERITINIB	4	BMPR1A
DASATINIB	4	BMPR1A
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	STK11
SUNITINIB	4	STK11
MIDOSTAURIN	4	STK11
SARACATINIB	3	BMPR1A
LESTAURTINIB	3	BMPR1A, STK11
DINACICLIB	3	STK11
DOVITINIB	3	STK11
RUBOXISTAURIN	3	STK11
AT-9283	2	BMPR1A
ZILURGISERTIB	2	BMPR1A
KER-047	2	BMPR1A
AZD-1480	2	STK11
SU-014813	2	STK11
R-406	2	STK11
TOZASERTIB	2	STK11
KW-2449	1	BMPR1A, STK11
XL-228	1	BMPR1A, STK11
Y-39983	1	BMPR1A
PF-00562271	1	STK11
PF-03758309	1	STK11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	BMPR1A, STK11
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	4	SMAD4, ADIRF, KLLN, ADIRF-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMAD4	6	—
ADIRF	0	—
KLLN	0	—
ADIRF-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00633607	Not specified	COMPLETED	Hereditary Colorectal and Associated Tumor Registry Study