Cowden syndrome 4

Summary

Cowden syndrome 4 (MONDO:0014046) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cowden syndrome 4
Mondo ID	MONDO:0014046
OMIM	615107
DOID	DOID:0081000
UMLS	C3554517
MedGen	767431
GARD	0016463
Is cancer (heuristic)	no

Also known as: Cowden disease caused by mutation in KLLN · Cowden syndrome 4 · Cowden syndrome type 4 · CWS4 · KLLN Cowden disease

Data availability: 9 ClinVar variants · 1 GenCC gene-disease record.

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 4

Related subtypes (7): Cowden syndrome 1, Cowden syndrome 2, Cowden syndrome 3, 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

9 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 likely benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
40164	NG_033079.1:g.4675_4964|gom	KLLN	Pathogenic	no assertion criteria provided
565960	NM_000314.8(PTEN):c.275A>G (p.Asp92Gly)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683532	NM_001126049.2(KLLN):c.226T>C (p.Phe76Leu)	KLLN	Uncertain significance	criteria provided, single submitter
1683533	NM_001126049.2(KLLN):c.526C>A (p.Pro176Thr)	KLLN	Uncertain significance	criteria provided, single submitter
234894	NC_000010.11:g.87863235C>T	KLLN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433170	NM_001126049.2(KLLN):c.184C>G (p.Arg62Gly)	KLLN	Uncertain significance	criteria provided, single submitter
127660	NM_001126049.2(KLLN):c.-898G>A	KLLN	Likely benign	reviewed by expert panel
127662	NM_001126049.2(KLLN):c.-812G>A	KLLN	Likely benign	reviewed by expert panel
138836	NM_001126049.2(KLLN):c.-956G>T	LOC130004273	Likely benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 16 · 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
KLLN	Supportive	Autosomal dominant	Cowden disease	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KLLN	Orphanet:201	Cowden syndrome
KLLN	Orphanet:227535	Hereditary breast cancer
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KLLN	HGNC:37212	ENSG00000227268	B2CW77	Killin	gencc,clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLLN	Killin	DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis.
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KLLN	Other/Unknown	no
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1
tibialis anterior	1
calcaneal tendon	1
endothelial cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLLN	149		marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTEN	11,626
KLLN	234

Intra-cohort edges

A	B	Sources
KLLN	PTEN	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTEN	P60484	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLLN	B2CW77	51.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PTEN Loss of Function in Cancer	1	5710.0×	0.002	PTEN
Regulation of PTEN mRNA translation	1	1142.0×	0.004	PTEN
Regulation of PTEN localization	1	1038.2×	0.004	PTEN
Synthesis of IP3 and IP4 in the cytosol	1	423.0×	0.007	PTEN
Transcriptional Regulation by MECP2	1	317.2×	0.007	PTEN
Negative regulation of the PI3K/AKT network	1	278.5×	0.007	PTEN
Ovarian tumor domain proteases	1	278.5×	0.007	PTEN
Synthesis of PIPs at the plasma membrane	1	211.5×	0.007	PTEN
Regulation of PTEN stability and activity	1	184.2×	0.007	PTEN
Regulation of PTEN gene transcription	1	178.4×	0.007	PTEN
TP53 Regulates Metabolic Genes	1	129.8×	0.008	PTEN
Downstream TCR signaling	1	128.3×	0.008	PTEN
Ub-specific processing proteases	1	53.1×	0.019	PTEN

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
negative regulation of synaptic vesicle clustering	1	4213.0×	0.004	PTEN
negative regulation of keratinocyte migration	1	2808.7×	0.004	PTEN
rhythmic synaptic transmission	1	2106.5×	0.004	PTEN
central nervous system myelin maintenance	1	1404.3×	0.004	PTEN
negative regulation of cell cycle G1/S phase transition	1	1203.7×	0.004	PTEN
negative regulation of wound healing, spreading of epidermal cells	1	1203.7×	0.004	PTEN
spindle assembly involved in female meiosis	1	936.2×	0.004	PTEN
central nervous system neuron axonogenesis	1	936.2×	0.004	PTEN
postsynaptic density assembly	1	936.2×	0.004	PTEN
neuron-neuron synaptic transmission	1	842.6×	0.004	PTEN
negative regulation of peptidyl-serine phosphorylation	1	842.6×	0.004	PTEN
negative regulation of cell size	1	842.6×	0.004	PTEN
presynaptic membrane assembly	1	842.6×	0.004	PTEN
negative regulation of organ growth	1	702.2×	0.004	PTEN
forebrain morphogenesis	1	702.2×	0.004	PTEN
multicellular organismal response to stress	1	648.1×	0.004	PTEN
negative regulation of axonogenesis	1	648.1×	0.004	PTEN
cellular response to electrical stimulus	1	648.1×	0.004	PTEN
negative regulation of excitatory postsynaptic potential	1	648.1×	0.004	PTEN
apoptotic process	2	28.7×	0.004	KLLN, PTEN
maternal behavior	1	561.7×	0.005	PTEN
prepulse inhibition	1	561.7×	0.005	PTEN
locomotor rhythm	1	526.6×	0.005	PTEN
synapse maturation	1	468.1×	0.005	PTEN
dendritic spine morphogenesis	1	443.5×	0.005	PTEN
negative regulation of focal adhesion assembly	1	383.0×	0.006	PTEN
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	351.1×	0.006	PTEN
negative regulation of vascular associated smooth muscle cell proliferation	1	337.0×	0.006	PTEN
phosphatidylinositol dephosphorylation	1	324.1×	0.006	PTEN
positive regulation of intracellular signal transduction	1	324.1×	0.006	PTEN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KLLN	0	0
PTEN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PTEN	8	Binding:8

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

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	1	PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KLLN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KLLN	0	—
PTEN	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.