Cowden syndrome 1

Summary

Cowden syndrome 1 (MONDO:0008021) is a disease caused by PTEN (GenCC Definitive), with 8 cohort genes and 1 clinical trial.

At a glance

• Causal gene: PTEN (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 1,047
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cowden syndrome 1
Mondo ID	MONDO:0008021
OMIM	158350
GARD	0016450
Is cancer (heuristic)	no

Also known as: Cowden disease caused by mutation in PTEN · Cowden syndrome 1 · Cowden syndrome type 1 · CS · CWS1 · Lhermitte-Duclos syndrome · PTEN Cowden disease

Data availability: 1,047 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 › Cowden disease › Cowden syndrome 1

Related subtypes (7): Cowden syndrome 2, Cowden syndrome 3, Cowden syndrome 4, Cowden syndrome 5, Cowden syndrome 6, Cowden syndrome 7, sacral hemangiomas multiple congenital abnormalities

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:

249 pathogenic, 105 benign/likely benign, 75 likely benign, 56 likely pathogenic, 36 uncertain significance, 32 conflicting classifications of pathogenicity, 29 pathogenic/likely pathogenic, 18 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
254143	NM_005228.5(EGFR):c.977G>T (p.Cys326Phe)	EGFR	Pathogenic	no assertion criteria provided
13653	NM_006218.4(PIK3CA):c.3140A>T (p.His1047Leu)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
1067089	NM_000314.8(PTEN):c.376G>C (p.Ala126Pro)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1067498	NM_000314.8(PTEN):c.493G>C (p.Gly165Arg)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069915	NM_000314.8(PTEN):c.184A>T (p.Lys62Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1075939	NM_000314.8(PTEN):c.250A>T (p.Arg84Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1076438	NM_001304718.2(PTEN):c.-541-5533del	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1195176	NM_000314.8(PTEN):c.379G>T (p.Gly127Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1212448	NM_000314.8(PTEN):c.492+1G>A	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330013	NM_000314.8(PTEN):c.672_673insC (p.Tyr225fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1333638	NM_000314.8(PTEN):c.493-1G>T	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338262	NM_000314.8(PTEN):c.373A>G (p.Lys125Glu)	PTEN	Pathogenic	reviewed by expert panel
1379224	NM_000314.8(PTEN):c.143A>G (p.Asn48Ser)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
139568	NM_000314.8(PTEN):c.379G>A (p.Gly127Arg)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141485	NM_000314.8(PTEN):c.493-2A>G	PTEN	Pathogenic	reviewed by expert panel
141654	NM_000314.8(PTEN):c.50_51del (p.Gln17fs)	PTEN	Pathogenic	reviewed by expert panel
142018	NM_000314.8(PTEN):c.389G>C (p.Arg130Pro)	PTEN	Pathogenic	reviewed by expert panel
142027	NM_000314.8(PTEN):c.48T>A (p.Tyr16Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
142259	NM_000314.8(PTEN):c.741dup (p.Pro248fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1422662	NM_000314.8(PTEN):c.43A>T (p.Arg15Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
142269	NM_000314.8(PTEN):c.737C>T (p.Pro246Leu)	PTEN	Pathogenic	reviewed by expert panel
142287	NM_000314.8(PTEN):c.403A>G (p.Ile135Val)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142423	NM_000314.8(PTEN):c.802-2A>T	PTEN	Pathogenic	reviewed by expert panel
142636	NM_000314.8(PTEN):c.493G>T (p.Gly165Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
142640	NM_000314.8(PTEN):c.822G>A (p.Trp274Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1453956	NM_000314.8(PTEN):c.201dup (p.Tyr68fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1454161	NM_000314.8(PTEN):c.270del (p.Phe90fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1457597	NM_000314.8(PTEN):c.287C>A (p.Pro96Gln)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458931	NM_000314.8(PTEN):c.1007dup (p.Tyr336Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1459040	NC_000010.11:g.87952119del	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 42 · 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
PTEN	Definitive	Autosomal dominant	Cowden syndrome 1	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTEN	Orphanet:109	Bannayan-Riley-Ruvalcaba syndrome
PTEN	Orphanet:137608	Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
PTEN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PTEN	Orphanet:201	Cowden syndrome
PTEN	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
PTEN	Orphanet:2969	Proteus-like syndrome
PTEN	Orphanet:494547	Squamous cell carcinoma of the hypopharynx
PTEN	Orphanet:494550	Squamous cell carcinoma of the larynx
PTEN	Orphanet:500464	Squamous cell carcinoma of the nasal cavity and paranasal sinuses
PTEN	Orphanet:500478	Squamous cell carcinoma of the oropharynx
PTEN	Orphanet:502363	Squamous cell carcinoma of the oral cavity
PTEN	Orphanet:502366	Squamous cell carcinoma of the lip
PTEN	Orphanet:65285	Lhermitte-Duclos disease
PTEN	Orphanet:79076	Juvenile polyposis of infancy
SDHB	Orphanet:139411	Carney triad
SDHB	Orphanet:201	Cowden syndrome
SDHB	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHB	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHB	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHB	Orphanet:44890	Gastrointestinal stromal tumor
SDHB	Orphanet:97286	Carney-Stratakis syndrome
COL18A1	Orphanet:1571	Knobloch syndrome
EGFR	Orphanet:251576	Gliosarcoma
EGFR	Orphanet:251579	Giant cell glioblastoma
KLLN	Orphanet:201	Cowden syndrome
KLLN	Orphanet:227535	Hereditary breast cancer
LDLR	Orphanet:391665	Homozygous familial hypercholesterolemia
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	gencc,clinvar
SDHB	HGNC:10681	ENSG00000117118	P21912	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	clinvar
COL18A1	HGNC:2195	ENSG00000182871	P39060	Collagen alpha-1(XVIII) chain	clinvar
EGFR	HGNC:3236	ENSG00000146648	P00533	Epidermal growth factor receptor	clinvar
KLLN	HGNC:37212	ENSG00000227268	B2CW77	Killin	clinvar
MLDHR	HGNC:55481	ENSG00000289051	C0HLV8	PTEN upstream open reading frame MP31	clinvar
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
SDHB	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	Iron-sulfur protein (IP) subunit of the succinate dehydrogenase complex (mitochondrial respiratory chain complex II), responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
COL18A1	Collagen alpha-1(XVIII) chain	Probably plays a major role in determining the retinal structure as well as in the closure of the neural tube.
EGFR	Epidermal growth factor receptor	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses.
KLLN	Killin	DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis.
MLDHR	PTEN upstream open reading frame MP31	Inhibits lactate dehydrogenase (LDH)-mediated conversion of lactate to pyruvate in mitochondria by competing with mitochondrial LDH for binding to NAD(+).
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.5

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	6.9×	0.126
Phosphatase	1	10.5×	0.183
Enzyme (other)	1	1.5×	0.669
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
SDHB	Enzyme (other)	yes	1.3.5.1	2Fe-2S_ferredoxin-type, Succ_DH/fum_Rdtase_Fe-S, 2Fe2S_fd_BS
COL18A1	Other/Unknown	no		Collagen, DUF959_COL18_N, Collagenase_NC10/endostatin
EGFR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
KLLN	Other/Unknown	no
MLDHR	Other/Unknown	no		MP31
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

Expression context

Cohort genes with no expression data: 1.

7 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)	7
unknown	1

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
adrenal tissue	2
endothelial cell	1
sperm	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
popliteal artery	1
right coronary artery	1
tibial artery	1
gingiva	1
gingival epithelium	1
nipple	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1
tibialis anterior	1
lower lobe of lung	1
right adrenal gland	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
SDHB	293	ubiquitous	marker	heart left ventricle, cardiac ventricle, apex of heart
COL18A1	266	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
EGFR	285	ubiquitous	marker	nipple, gingiva, gingival epithelium
KLLN	149		marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
MLDHR
LDLR	281	ubiquitous	marker	adrenal tissue, lower lobe of lung, right adrenal gland
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGFR	18,421
PTEN	11,626
SDHB	5,471
PIK3CA	5,157
COL18A1	2,316
LDLR	1,426
KLLN	234
MLDHR	0

Intra-cohort edges

A	B	Sources
EGFR	LDLR	string_interaction
EGFR	PIK3CA	string_interaction
EGFR	PTEN	string_interaction
KLLN	PIK3CA	string_interaction
KLLN	PTEN	string_interaction
KLLN	SDHB	string_interaction
PIK3CA	PTEN	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EGFR	P00533	388
PIK3CA	P42336	135
LDLR	P01130	36
PTEN	P60484	12
COL18A1	P39060	9
SDHB	P21912	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MLDHR	C0HLV8	83.86
KLLN	B2CW77	51.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 121. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Constitutive Signaling by EGFRvIII	2	237.9×	0.001	EGFR, PIK3CA
PI3K events in ERBB2 signaling	2	223.9×	0.001	EGFR, PIK3CA
Signaling by ERBB2 ECD mutants	2	223.9×	0.001	EGFR, PIK3CA
GAB1 signalosome	2	211.5×	0.001	EGFR, PIK3CA
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	2	190.3×	0.001	EGFR, PIK3CA
Signaling by ERBB2 KD Mutants	2	141.0×	0.002	EGFR, PIK3CA
Synthesis of PIPs at the plasma membrane	2	70.5×	0.006	PTEN, PIK3CA
Extra-nuclear estrogen signaling	2	56.8×	0.008	EGFR, PIK3CA
Downstream TCR signaling	2	42.8×	0.011	PTEN, PIK3CA
Constitutive Signaling by Aberrant PI3K in Cancer	2	42.3×	0.011	EGFR, PIK3CA
PTEN Loss of Function in Cancer	1	951.7×	0.012	PTEN
Cargo recognition for clathrin-mediated endocytosis	2	34.9×	0.013	EGFR, LDLR
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	32.3×	0.014	EGFR, PIK3CA
PLCG1 events in ERBB2 signaling	1	475.8×	0.017	EGFR
Clathrin-mediated endocytosis	2	28.4×	0.017	EGFR, LDLR
Chylomicron clearance	1	380.7×	0.020	LDLR
MET activates PI3K/AKT signaling	1	317.2×	0.020	PIK3CA
Activated NTRK3 signals through PI3K	1	317.2×	0.020	PIK3CA
PTK6 promotes HIF1A stabilization	1	271.9×	0.020	EGFR
Activated NTRK2 signals through PI3K	1	271.9×	0.020	PIK3CA
Signaling by LTK in cancer	1	271.9×	0.020	PIK3CA
PIP3 activates AKT signaling	2	22.3×	0.020	EGFR, PIK3CA
RAF/MAP kinase cascade	2	20.4×	0.020	EGFR, PIK3CA
PI3K/AKT activation	1	211.5×	0.022	PIK3CA
Inhibition of Signaling by Overexpressed EGFR	1	211.5×	0.022	EGFR
EGFR interacts with phospholipase C-gamma	1	190.3×	0.022	EGFR
EGFR Transactivation by Gastrin	1	190.3×	0.022	EGFR
Regulation of PTEN mRNA translation	1	190.3×	0.022	PTEN
IRS-mediated signalling	1	173.0×	0.022	PIK3CA
PI3K events in ERBB4 signaling	1	173.0×	0.022	PIK3CA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phosphatidylinositol 3-kinase/protein kinase B signal transduction	3	79.0×	0.001	PTEN, EGFR, PIK3CA
response to muscle inactivity	1	2106.5×	0.014	PIK3CA
response to butyrate	1	2106.5×	0.014	PIK3CA
negative regulation of cardiocyte differentiation	1	2106.5×	0.014	EGFR
epidermal growth factor receptor signaling pathway	2	62.0×	0.014	EGFR, PIK3CA
phagocytosis	2	60.2×	0.014	LDLR, PIK3CA
learning or memory	2	60.2×	0.014	PTEN, EGFR
regulation of phosphatidylcholine catabolic process	1	1053.2×	0.017	LDLR
receptor-mediated endocytosis involved in cholesterol transport	1	1053.2×	0.017	LDLR
negative regulation of synaptic vesicle clustering	1	1053.2×	0.017	PTEN
response to L-leucine	1	702.2×	0.017	PIK3CA
negative regulation of keratinocyte migration	1	702.2×	0.017	PTEN
negative regulation of astrocyte activation	1	702.2×	0.017	LDLR
cellular response to hydrostatic pressure	1	702.2×	0.017	PIK3CA
positive regulation of protein kinase C signaling	1	702.2×	0.017	EGFR
plasma lipoprotein particle clearance	1	526.6×	0.017	LDLR
response to hydrostatic pressure	1	526.6×	0.017	COL18A1
rhythmic synaptic transmission	1	526.6×	0.017	PTEN
morphogenesis of an epithelial fold	1	526.6×	0.017	EGFR
response to UV-A	1	526.6×	0.017	EGFR
negative regulation of receptor recycling	1	421.3×	0.017	LDLR
succinate metabolic process	1	421.3×	0.017	SDHB
mitochondrial electron transport, succinate to ubiquinone	1	421.3×	0.017	SDHB
regulation of peptidyl-tyrosine phosphorylation	1	421.3×	0.017	EGFR
positive regulation of lysosomal protein catabolic process	1	421.3×	0.017	LDLR
negative regulation of actin filament depolymerization	1	351.1×	0.017	PIK3CA
central nervous system myelin maintenance	1	351.1×	0.017	PTEN
regulation of cellular respiration	1	351.1×	0.017	PIK3CA
cholesterol import	1	351.1×	0.017	LDLR
salivary gland morphogenesis	1	300.9×	0.017	EGFR

Therapeutics

Drug target analysis

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

Druggability breadth: 6 of 8 evidence-associated genes (75%) 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
EGFR	LEVODOPA
LDLR	NILOTINIB
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EGFR	175	4
PIK3CA	67	4
LDLR	1	4
PTEN	0	0
SDHB	0	0
COL18A1	0	0
KLLN	0	0
MLDHR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVODOPA	4	EGFR
CLOTRIMAZOLE	4	EGFR
ERLOTINIB HYDROCHLORIDE	4	EGFR
CISPLATIN	4	EGFR
PONATINIB	4	EGFR
AFATINIB	4	EGFR
CHROMIC CHLORIDE	4	EGFR
BACITRACIN	4	EGFR
ZINC CHLORIDE	4	EGFR
LAPATINIB DITOSYLATE	4	EGFR
VEMURAFENIB	4	EGFR
FEDRATINIB	4	EGFR, PIK3CA
AXITINIB	4	EGFR
SORAFENIB	4	EGFR
DASATINIB ANHYDROUS	4	EGFR
NICLOSAMIDE	4	EGFR
SELUMETINIB	4	EGFR
TERFENADINE	4	EGFR
ALECTINIB	4	EGFR
NERATINIB	4	EGFR
IBRUTINIB	4	EGFR
AFATINIB DIMALEATE	4	EGFR
CABOZANTINIB	4	EGFR
DACOMITINIB	4	EGFR
DACOMITINIB ANHYDROUS	4	EGFR
CERITINIB	4	EGFR
VANDETANIB	4	EGFR
TRIBROMSALAN	4	EGFR
BOSUTINIB	4	EGFR
BITHIONOL	4	EGFR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
EGFR	6,531	Binding:6211, Functional:173, ADMET:138, Toxicity:9
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
LDLR	55	Binding:54, Functional:1
PTEN	8	Binding:8
SDHB	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase
SDHB	1.3.5.1	succinate dehydrogenase
EGFR	2.7.10.1	receptor protein-tyrosine kinase
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, 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
EGFR	6,531
PIK3CA	2,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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)
LEVODOPA	4	EGFR
CLOTRIMAZOLE	4	EGFR
ERLOTINIB HYDROCHLORIDE	4	EGFR
CISPLATIN	4	EGFR
PONATINIB	4	EGFR
AFATINIB	4	EGFR
CHROMIC CHLORIDE	4	EGFR
BACITRACIN	4	EGFR
ZINC CHLORIDE	4	EGFR
LAPATINIB DITOSYLATE	4	EGFR
VEMURAFENIB	4	EGFR
FEDRATINIB	4	EGFR, PIK3CA
AXITINIB	4	EGFR
SORAFENIB	4	EGFR
DASATINIB ANHYDROUS	4	EGFR
NICLOSAMIDE	4	EGFR
SELUMETINIB	4	EGFR
TERFENADINE	4	EGFR
ALECTINIB	4	EGFR
NERATINIB	4	EGFR
IBRUTINIB	4	EGFR
AFATINIB DIMALEATE	4	EGFR
CABOZANTINIB	4	EGFR
DACOMITINIB	4	EGFR
DACOMITINIB ANHYDROUS	4	EGFR
CERITINIB	4	EGFR
VANDETANIB	4	EGFR
TRIBROMSALAN	4	EGFR
BOSUTINIB	4	EGFR
BITHIONOL	4	EGFR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	EGFR, LDLR, PIK3CA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	PTEN, SDHB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	COL18A1, KLLN, MLDHR

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)
PTEN	8	—
SDHB	4	—
COL18A1	0	—
KLLN	0	—
MLDHR	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
NCT06622733	Not specified	RECRUITING	Attitude Towards the Concept of CS on Demand