NK-cell enteropathy

Summary

NK-cell enteropathy (MONDO:0016996) is a disease with 13 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 13
• ClinVar variants: 13
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000969	Edema	Very frequent (80-99%)
HP:0005523	Lymphoproliferative disorder	Very frequent (80-99%)
HP:0100828	Increased T cell count	Very frequent (80-99%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002253	Colonic diverticula	Occasional (5-29%)
HP:0002573	Hematochezia	Occasional (5-29%)
HP:0002588	Duodenal ulcer	Occasional (5-29%)
HP:0002592	Gastric ulcer	Occasional (5-29%)
HP:0004295	Abnormality of the gastric mucosa	Occasional (5-29%)
HP:0005266	Intestinal polyp	Occasional (5-29%)
HP:0012425	Stercoral ulcer	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	NK-cell enteropathy
Mondo ID	MONDO:0016996
Orphanet	263665
SNOMED CT	723496007
UMLS	C4509932
MedGen	1379183
GARD	0020905
Is cancer (heuristic)	no

Data availability: 13 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › intestinal disorder › NK-cell enteropathy

Related subtypes (57): intestinal atresia, steatorrhea, angiodysplasia of intestine, endometriosis of intestine, hypertrophic pyloric stenosis, mucocele of appendix, gastroenteritis, diverticulitis, intestinal obstruction, postgastrectomy syndrome, chronic intestinal vascular insufficiency, bowel dysfunction, irritable bowel syndrome, Whipple disease, inflammatory bowel disease, intestinal polyp, necrotizing enterocolitis, intestinal perforation, neurogenic bowel, pneumatosis cystoides intestinalis, volvulus of midgut, abetalipoproteinemia, aplasia cutis congenita-intestinal lymphangiectasia syndrome, trichohepatoenteric syndrome, protein-losing enteropathy, chronic diarrhea with villous atrophy, Satoyoshi syndrome, glucose-galactose malabsorption, congenital diarrhea 7 with exudative enteropathy, chronic atrial and intestinal dysrhythmia, congenital enterocyte heparan sulfate deficiency, short bowel syndrome, intractable diarrhea-choanal atresia-eye anomalies syndrome, solitary rectal ulcer syndrome, chronic intestinal failure, intestinal lymphangiectasia, refractory celiac disease, eosinophilic gastrointestinal disease, cryptogenic multifocal ulcerous stenosing enteritis, chronic enteropathy associated with SLCO2A1 gene, cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder, malakoplakia, malabsorption syndrome, ischemic bowel disorder, intestinal neoplasm, intestinal motility disease, 4-hydroxyphenylacetic aciduria, parasitic intestinal disorder, Aeromonas hydrophila intestinal disease, large intestine disorder, small intestine disorder, primary desmosis coli, isolated mesenteric vein thrombosis, collagenous sprue, visceral leiomyopathy, African degenerative, intestinal dysmotility syndrome, intestinal fistula

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

13 retrieved; paginated sample, class counts are floors:

9 likely pathogenic, 3 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
638620	NM_000215.4(JAK3):c.1688_1696del (p.Lys563_Cys565del)	JAK3	Pathogenic	no assertion criteria provided
638622	NM_004217.4(AURKB):c.847C>T (p.Arg283Cys)	AURKB	Likely pathogenic	no assertion criteria provided
638632	NM_021913.5(AXL):c.2161C>G (p.Leu721Val)	AXL	Likely pathogenic	no assertion criteria provided
638623	NM_003590.5(CUL3):c.1499G>A (p.Gly500Asp)	CUL3	Likely pathogenic	no assertion criteria provided
638628	NM_005235.3(ERBB4):c.785G>A (p.Cys262Tyr)	ERBB4	Likely pathogenic	no assertion criteria provided
638629	NM_000875.5(IGF1R):c.3464G>A (p.Gly1155Asp)	IGF1R	Likely pathogenic	no assertion criteria provided
638630	NM_006219.3(PIK3CB):c.2961G>T (p.Glu987Asp)	PIK3CB	Likely pathogenic	no assertion criteria provided
638621	NM_002850.4(PTPRS):c.4756G>A (p.Val1586Met)	PTPRS	Likely pathogenic	no assertion criteria provided
638625	NM_175635.3(RUNX1T1):c.127A>C (p.Thr43Pro)	RUNX1T1	Likely pathogenic	no assertion criteria provided
638627	NM_003073.5(SMARCB1):c.1129C>G (p.Arg377Gly)	SMARCB1	Likely pathogenic	no assertion criteria provided
638624	NM_007194.4(CHEK2):c.1421G>T (p.Arg474Leu)	CHEK2	Uncertain significance	criteria provided, single submitter
638626	NM_001386298.1(CIC):c.7506dup (p.Pro2503fs)	CIC	Uncertain significance	criteria provided, single submitter
638631	NM_001080517.3(SETD5):c.2837C>T (p.Pro946Leu)	SETD5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 21 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCB1	Orphanet:1465	Coffin-Siris syndrome
SMARCB1	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCB1	Orphanet:2495	Meningioma
SMARCB1	Orphanet:263662	Familial multiple meningioma
SMARCB1	Orphanet:93921	Full schwannomatosis
SMARCB1	Orphanet:99966	Atypical teratoid rhabdoid tumor
CIC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
RUNX1T1	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
CHEK2	Orphanet:1331	Familial prostate cancer
CHEK2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
CHEK2	Orphanet:440437	Familial colorectal cancer Type X
CHEK2	Orphanet:524	Li-Fraumeni syndrome
CHEK2	Orphanet:668	Osteosarcoma
CUL3	Orphanet:300530	Pseudohypoaldosteronism type 2E
CUL3	Orphanet:528084	Non-specific syndromic intellectual disability
SETD5	Orphanet:435638	3p25.3 microdeletion syndrome
SETD5	Orphanet:528084	Non-specific syndromic intellectual disability
ERBB4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ERBB4	Orphanet:803	Amyotrophic lateral sclerosis
IGF1R	Orphanet:73273	Growth delay due to insulin-like growth factor I resistance
JAK3	Orphanet:35078	T-B+ severe combined immunodeficiency due to JAK3 deficiency

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCB1	HGNC:11103	ENSG00000099956	Q12824	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	clinvar
AURKB	HGNC:11390	ENSG00000178999	Q96GD4	Aurora kinase B	clinvar
CIC	HGNC:14214	ENSG00000079432	Q96RK0	Protein capicua homolog	clinvar
RUNX1T1	HGNC:1535	ENSG00000079102	Q06455	Protein CBFA2T1	clinvar
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar
CUL3	HGNC:2553	ENSG00000036257	Q13618	Cullin-3	clinvar
SETD5	HGNC:25566	ENSG00000168137	Q9C0A6	Histone-lysine N-methyltransferase SETD5	clinvar
ERBB4	HGNC:3432	ENSG00000178568	Q15303	Receptor tyrosine-protein kinase erbB-4	clinvar
IGF1R	HGNC:5465	ENSG00000140443	P08069	Insulin-like growth factor 1 receptor	clinvar
JAK3	HGNC:6193	ENSG00000105639	P52333	Tyrosine-protein kinase JAK3	clinvar
PIK3CB	HGNC:8976	ENSG00000051382	P42338	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform	clinvar
AXL	HGNC:905	ENSG00000167601	P30530	Tyrosine-protein kinase receptor UFO	clinvar
PTPRS	HGNC:9681	ENSG00000105426	Q13332	Receptor-type tyrosine-protein phosphatase S	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCB1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	Core component of the BAF (hSWI/SNF) complex.
AURKB	Aurora kinase B	Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis.
CIC	Protein capicua homolog	Transcriptional repressor which plays a role in development of the central nervous system (CNS).
RUNX1T1	Protein CBFA2T1	Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
CUL3	Cullin-3	Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
SETD5	Histone-lysine N-methyltransferase SETD5	Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission.
ERBB4	Receptor tyrosine-protein kinase erbB-4	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell prolife…
IGF1R	Insulin-like growth factor 1 receptor	Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1).
JAK3	Tyrosine-protein kinase JAK3	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation.
PIK3CB	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.
AXL	Tyrosine-protein kinase receptor UFO	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migratio…
PTPRS	Receptor-type tyrosine-protein phosphatase S	Cell surface receptor that binds to glycosaminoglycans, including chondroitin sulfate proteoglycans and heparan sulfate proteoglycan.

Protein-family classification

Druggable: 8 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.62

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	7	14.9×	4e-07
Phosphatase	1	6.5×	0.289
Transcription factor	1	0.6×	0.982
Other/Unknown	4	0.6×	0.982

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCB1	Other/Unknown	no		SNF5, Sfh1/SNF5, INI1_DNA-bd
AURKB	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CIC	Other/Unknown	no		HMG_box_dom, Cic_dom, HMG_box_dom_sf
RUNX1T1	Transcription factor	no		Znf_MYND, TAFH_NHR1, CBFA2T1/2/3
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
CUL3	Other/Unknown	no		Cullin_N, Cullin_CS, Cullin_homology
SETD5	Other/Unknown	no		SET_dom, SETD5_SET, SET_dom_sf
ERBB4	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
IGF1R	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
JAK3	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
PIK3CB	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
AXL	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub
PTPRS	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat

Expression context

Cohort genes with no expression data: 0.

13 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	3
sural nerve	3
cortical plate	2
oocyte	2
secondary oocyte	2
adrenal tissue	2
endothelial cell	2
embryo	1
ventricular zone	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
left testis	1
male germ cell	1
sperm	1
colonic epithelium	1
cranial nerve II	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCB1	214	ubiquitous	marker	embryo, ganglionic eminence, cortical plate
AURKB	187	ubiquitous	marker	ventricular zone, ganglionic eminence, oocyte
CIC	274	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
RUNX1T1	274	ubiquitous	marker	secondary oocyte, oocyte, sural nerve
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
CUL3	296	ubiquitous	marker	sperm, male germ cell, left testis
SETD5	284	ubiquitous	marker	adrenal tissue, colonic epithelium, sural nerve
ERBB4	226	broad	marker	endothelial cell, secondary oocyte, cranial nerve II
IGF1R	285	ubiquitous	marker	caput epididymis, corpus epididymis, adrenal tissue
JAK3	219	ubiquitous	marker	granulocyte, blood, spleen
PIK3CB	294	ubiquitous	marker	tendon of biceps brachii, medial globus pallidus, endothelial cell
AXL	290	ubiquitous	marker	synovial joint, saphenous vein, stromal cell of endometrium
PTPRS	173	ubiquitous	marker	cortical plate, ganglionic eminence, sural nerve

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CUL3	9,954
IGF1R	6,823
AURKB	6,131
SMARCB1	5,083
CHEK2	4,795
AXL	4,443
ERBB4	4,325
JAK3	3,630
PIK3CB	2,505
RUNX1T1	2,492

Intra-cohort edges

A	B	Sources
AURKB	CUL3	biogrid_interaction
CIC	ERBB4	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IGF1R	P08069	46
JAK3	P52333	42
CHEK2	O96017	38
CUL3	Q13618	30
SMARCB1	Q12824	17
ERBB4	Q15303	14
RUNX1T1	Q06455	9
CIC	Q96RK0	7
PTPRS	Q13332	6
AXL	P30530	4
AURKB	Q96GD4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIK3CB	P42338	86.62
SETD5	Q9C0A6	47.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 144. Enrichment computed across 13 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by ALK	2	114.2×	0.017	JAK3, PIK3CB
Interleukin receptor SHC signaling	2	81.6×	0.017	JAK3, PIK3CB
Interleukin-3, Interleukin-5 and GM-CSF signaling	2	63.4×	0.017	JAK3, PIK3CB
RAF/MAP kinase cascade	3	18.3×	0.017	ERBB4, JAK3, PIK3CB
Signaling by LTK in cancer	1	163.1×	0.057	PIK3CB
PI3K/AKT activation	1	126.9×	0.057	PIK3CB
Interleukin-9 signaling	1	126.9×	0.057	JAK3
Downregulation of ERBB4 signaling	1	114.2×	0.057	ERBB4
SHC-related events triggered by IGF1R	1	114.2×	0.057	IGF1R
Interleukin-21 signaling	1	114.2×	0.057	JAK3
Signaling by NTRK3 (TRKC)	1	114.2×	0.057	PTPRS
RHOBTB3 ATPase cycle	1	114.2×	0.057	CUL3
IRS-mediated signalling	1	103.8×	0.057	PIK3CB
PI3K events in ERBB4 signaling	1	103.8×	0.057	ERBB4
IRS-related events triggered by IGF1R	1	103.8×	0.057	IGF1R
Co-stimulation by ICOS	1	103.8×	0.057	PIK3CB
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	95.2×	0.057	IGF1R
Interleukin-2 signaling	1	95.2×	0.057	JAK3
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	95.2×	0.057	PIK3CB
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	87.8×	0.057	PIK3CB
Signaling by PDGFRA extracellular domain mutants	1	87.8×	0.057	PIK3CB
Signaling by LTK	1	87.8×	0.057	PIK3CB
ERBB2 Activates PTK6 Signaling	1	81.6×	0.057	ERBB4
Stabilization of p53	1	76.1×	0.057	CHEK2
Interleukin-15 signaling	1	76.1×	0.057	JAK3
SHC1 events in ERBB4 signaling	1	71.4×	0.057	ERBB4
ERBB2 Regulates Cell Motility	1	71.4×	0.057	ERBB4
PI3K events in ERBB2 signaling	1	67.2×	0.057	ERBB4
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	1	67.2×	0.057	CHEK2
GRB2 events in ERBB2 signaling	1	63.4×	0.057	ERBB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic cleavage	2	259.3×	0.005	CUL3, PIK3CB
cell surface receptor protein tyrosine kinase signaling pathway	3	40.1×	0.005	ERBB4, PIK3CB, AXL
cell migration	4	18.9×	0.005	CUL3, ERBB4, PIK3CB, AXL
protein autophosphorylation	3	33.5×	0.006	CHEK2, ERBB4, IGF1R
negative regulation of dendritic cell cytokine production	1	1296.3×	0.019	JAK3
single stranded viral RNA replication via double stranded DNA intermediate	1	1296.3×	0.019	SMARCB1
positive regulation of lateral attachment of mitotic spindle microtubules to kinetochore	1	1296.3×	0.019	AURKB
positive regulation of cytokinesis	2	61.7×	0.019	AURKB, CUL3
regulation of signal transduction by p53 class mediator	2	58.9×	0.019	AURKB, CHEK2
mitotic spindle assembly	2	52.9×	0.019	AURKB, CHEK2
negative regulation of MAPK cascade	2	46.3×	0.019	IGF1R, PIK3CB
cell surface receptor signaling pathway via JAK-STAT	2	44.7×	0.019	ERBB4, JAK3
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	3	18.1×	0.019	ERBB4, IGF1R, AXL
signal transduction	5	6.2×	0.019	ERBB4, IGF1R, PIK3CB, AXL, PTPRS
trophectodermal cellular morphogenesis	1	648.1×	0.020	CUL3
central nervous system morphogenesis	1	648.1×	0.020	ERBB4
response to interleukin-15	1	648.1×	0.020	JAK3
response to interleukin-9	1	648.1×	0.020	JAK3
establishment of planar polarity involved in nephron morphogenesis	1	648.1×	0.020	ERBB4
liver morphogenesis	1	648.1×	0.020	CUL3
repair of mitotic kinetochore microtubule attachment defect	1	648.1×	0.020	AURKB
mitotic sister chromatid biorientation	1	648.1×	0.020	AURKB
platelet activation	2	41.1×	0.020	PIK3CB, AXL
forebrain cell migration	1	432.1×	0.020	AXL
cell cycle G2/M phase transition	1	432.1×	0.020	AURKB
negative regulation of lymphocyte activation	1	432.1×	0.020	AXL
positive regulation of mitotic sister chromatid segregation	1	432.1×	0.020	AURKB
response to interleukin-2	1	432.1×	0.020	JAK3
trans-synaptic signaling	1	432.1×	0.020	PTPRS
regulation protein catabolic process at postsynapse	1	432.1×	0.020	CUL3

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 8 · Undrugged: 5

Druggability breadth: 10 of 13 evidence-associated genes (77%) 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
AURKB	SORAFENIB TOSYLATE
CHEK2	NERATINIB
ERBB4	MOBOCERTINIB
IGF1R	FEDRATINIB
JAK3	MOMELOTINIB
PIK3CB	IDELALISIB
AXL	GILTERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JAK3	91	4
AURKB	82	4
AXL	59	4
PIK3CB	53	4
ERBB4	47	4
CHEK2	30	4
IGF1R	27	4
PTPRS	1	2
SMARCB1	0	0
CIC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SORAFENIB TOSYLATE	4	AURKB
FEDRATINIB	4	AURKB, AXL, ERBB4, IGF1R, JAK3
TIVOZANIB	4	AURKB
LENVATINIB	4	AURKB
AXITINIB	4	AURKB, AXL, JAK3
SORAFENIB	4	AURKB, AXL, JAK3
ENTRECTINIB	4	AURKB, AXL, IGF1R, JAK3
BELUMOSUDIL	4	AURKB
PACRITINIB	4	AURKB, JAK3
FOSTAMATINIB	4	AURKB
TOFACITINIB	4	AURKB, JAK3
VANDETANIB	4	AURKB, AXL, ERBB4
UPADACITINIB	4	AURKB, JAK3
PEXIDARTINIB	4	AURKB
PAZOPANIB	4	AURKB, IGF1R, JAK3
NINTEDANIB	4	AURKB, AXL, IGF1R, JAK3
SUNITINIB	4	AURKB, AXL, CHEK2, IGF1R, JAK3
DASATINIB	4	AURKB, AXL, ERBB4, JAK3
ERLOTINIB	4	AURKB, AXL, ERBB4, JAK3
LAPATINIB	4	AURKB, ERBB4
QUIZARTINIB	4	AURKB, AXL
CRIZOTINIB	4	AURKB, AXL, IGF1R, JAK3
MIDOSTAURIN	4	AURKB, AXL, ERBB4, JAK3
INAMRINONE	4	AURKB
CABOZANTINIB	4	AURKB, AXL
NERATINIB	4	AXL, CHEK2, ERBB4, JAK3
BOSUTINIB	4	AXL, CHEK2, ERBB4, JAK3
BRIGATINIB	4	CHEK2, ERBB4, IGF1R
GEFITINIB	4	AXL, CHEK2, ERBB4
MOBOCERTINIB	4	ERBB4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
JAK3	1,461	Binding:1400, Functional:37, ADMET:22, Toxicity:2
AURKB	1,227	Binding:1199, ADMET:22, Functional:6
IGF1R	1,091	Binding:1037, Functional:53, ADMET:1
PIK3CB	841	Binding:814, ADMET:20, Functional:6, Toxicity:1
AXL	701	Binding:698, Functional:3
CHEK2	690	Binding:687, Functional:2, ADMET:1
ERBB4	591	Binding:579, ADMET:8, Functional:4
PTPRS	17	Binding:17
SMARCB1	7	Binding:7
CUL3	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
ERBB4	2.7.10.1	receptor protein-tyrosine kinase
IGF1R	2.7.10.1	receptor protein-tyrosine kinase
JAK3	2.7.10.2	non-specific protein-tyrosine kinase
PIK3CB	2.7.1.137, 2.7.1.153	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase
AXL	2.7.10.1	receptor protein-tyrosine kinase
PTPRS	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
AURKB	1,227
CHEK2	690
ERBB4	591
IGF1R	1,091
JAK3	1,461
PIK3CB	841
AXL	701

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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)
SORAFENIB TOSYLATE	4	AURKB
FEDRATINIB	4	AURKB, AXL, ERBB4, IGF1R, JAK3
TIVOZANIB	4	AURKB
LENVATINIB	4	AURKB
AXITINIB	4	AURKB, AXL, JAK3
SORAFENIB	4	AURKB, AXL, JAK3
ENTRECTINIB	4	AURKB, AXL, IGF1R, JAK3
BELUMOSUDIL	4	AURKB
PACRITINIB	4	AURKB, JAK3
FOSTAMATINIB	4	AURKB
TOFACITINIB	4	AURKB, JAK3
VANDETANIB	4	AURKB, AXL, ERBB4
UPADACITINIB	4	AURKB, JAK3
PEXIDARTINIB	4	AURKB
PAZOPANIB	4	AURKB, IGF1R, JAK3
NINTEDANIB	4	AURKB, AXL, IGF1R, JAK3
SUNITINIB	4	AURKB, AXL, CHEK2, IGF1R, JAK3
DASATINIB	4	AURKB, AXL, ERBB4, JAK3
ERLOTINIB	4	AURKB, AXL, ERBB4, JAK3
LAPATINIB	4	AURKB, ERBB4
QUIZARTINIB	4	AURKB, AXL
CRIZOTINIB	4	AURKB, AXL, IGF1R, JAK3
MIDOSTAURIN	4	AURKB, AXL, ERBB4, JAK3
INAMRINONE	4	AURKB
CABOZANTINIB	4	AURKB, AXL
NERATINIB	4	AXL, CHEK2, ERBB4, JAK3
BOSUTINIB	4	AXL, CHEK2, ERBB4, JAK3
BRIGATINIB	4	CHEK2, ERBB4, IGF1R
GEFITINIB	4	AXL, CHEK2, ERBB4
MOBOCERTINIB	4	ERBB4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	AURKB, CHEK2, ERBB4, IGF1R, JAK3, PIK3CB, AXL
B	Phased (≥1) drug, not yet approved	1	PTPRS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	SMARCB1, CIC, RUNX1T1, CUL3, SETD5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMARCB1	7	—
CIC	0	—
RUNX1T1	0	—
CUL3	7	—
SETD5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.