Cowden syndrome 3

Summary

Cowden syndrome 3 (MONDO:0014045) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 678

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cowden syndrome 3
Mondo ID	MONDO:0014045
OMIM	615106
GARD	0024966
Is cancer (heuristic)	no

Also known as: Cowden disease caused by mutation in SDHD · Cowden syndrome 3 · Cowden syndrome type 3 · CWS3 · SDHD Cowden disease

Data availability: 678 ClinVar variants.

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 3

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

277 uncertain significance, 127 likely benign, 74 pathogenic, 57 benign/likely benign, 40 conflicting classifications of pathogenicity, 18 pathogenic/likely pathogenic, 6 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424604	NC_000011.9:g.(?111171709)(111958707_?)del	DIXDC1	Pathogenic	criteria provided, single submitter
1319258	NM_003002.4(SDHD):c.49C>T (p.Arg17Ter)	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
1746035	NM_003002.4(SDHD):c.52+1_52+2delinsAA	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
239460	NM_003002.4(SDHD):c.10dup (p.Leu4fs)	LOC126861339	Pathogenic	criteria provided, single submitter
2925495	NM_003002.4(SDHD):c.2T>C (p.Met1Thr)	LOC126861339	Pathogenic	criteria provided, single submitter
3757250	NM_003002.4(SDHD):c.52+1G>T	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
547769	NM_003002.4(SDHD):c.18_21del (p.Leu7fs)	LOC126861339	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
584168	NC_000011.10:g.(?112086898)(112094980_?)del	LOC126861339	Pathogenic	criteria provided, single submitter
618362	NM_003002.4(SDHD):c.13_14del (p.Trp5fs)	LOC126861339	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6906	NM_003002.4(SDHD):c.3G>C (p.Met1Ile)	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
6911	NM_003002.4(SDHD):c.1A>G (p.Met1Val)	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
6915	NM_003002.4(SDHD):c.33C>A (p.Cys11Ter)	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
1076624	NC_000011.9:g.(?111957547)(111958707_?)del	SDHD	Pathogenic	criteria provided, single submitter
1372650	NM_003002.4(SDHD):c.281_282insAATA (p.Leu95fs)	SDHD	Pathogenic	criteria provided, single submitter
1381354	NC_000011.9:g.(?111957632)(111965694_?)del	SDHD	Pathogenic	criteria provided, single submitter
1401809	NM_003002.4(SDHD):c.317G>A (p.Gly106Asp)	SDHD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405955	NM_003002.4(SDHD):c.283del (p.Leu95fs)	SDHD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142068	NM_003002.4(SDHD):c.155C>A (p.Ser52Ter)	SDHD	Pathogenic	criteria provided, multiple submitters, no conflicts
1430410	NM_003002.4(SDHD):c.288del (p.Ala97fs)	SDHD	Pathogenic	criteria provided, single submitter
1453077	NM_003002.4(SDHD):c.169+1G>T	SDHD	Pathogenic	criteria provided, single submitter
1455596	NM_003002.4(SDHD):c.169+1G>A	SDHD	Pathogenic	criteria provided, single submitter
1457320	NM_003002.4(SDHD):c.224del (p.Leu75fs)	SDHD	Pathogenic	criteria provided, single submitter
1458129	NC_000011.9:g.(?111959581)(111965694_?)del	SDHD	Pathogenic	criteria provided, single submitter
1731167	NM_003002.4(SDHD):c.341_342del (p.Tyr114fs)	SDHD	Pathogenic	criteria provided, multiple submitters, no conflicts
185719	NM_003002.4(SDHD):c.304C>A (p.His102Asn)	SDHD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186590	NM_003002.4(SDHD):c.298_301del (p.Thr100fs)	SDHD	Pathogenic	criteria provided, multiple submitters, no conflicts
187700	NM_003002.4(SDHD):c.412G>A (p.Gly138Arg)	SDHD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1917924	NM_003002.4(SDHD):c.15G>A (p.Trp5Ter)	SDHD	Pathogenic	criteria provided, multiple submitters, no conflicts
2024310	NM_003002.4(SDHD):c.315-2A>T	SDHD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2035265	NM_003002.4(SDHD):c.136_143del (p.Val46fs)	SDHD	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHD	Orphanet:100093	Carcinoid syndrome
SDHD	Orphanet:201	Cowden syndrome
SDHD	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHD	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHD	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHD	Orphanet:97286	Carney-Stratakis syndrome
ALG9	Orphanet:730	Autosomal dominant polycystic kidney disease
ALG9	Orphanet:79328	ALG9-CDG

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHD	HGNC:10683	ENSG00000204370	O14521	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	clinvar
TIMM8B	HGNC:11818	ENSG00000150779	Q9Y5J9	Mitochondrial import inner membrane translocase subunit Tim8 B	clinvar
ALG9	HGNC:15672	ENSG00000086848	Q9H6U8	Alpha-1,2-mannosyltransferase ALG9	clinvar
DIXDC1	HGNC:23695	ENSG00000150764	Q155Q3	Dixin	clinvar
HOATZ	HGNC:25061	ENSG00000183644	Q6PI97	Cilia- and flagella-associated protein HOATZ	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHD	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
TIMM8B	Mitochondrial import inner membrane translocase subunit Tim8 B	Probable mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane.
ALG9	Alpha-1,2-mannosyltransferase ALG9	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
DIXDC1	Dixin	Positive effector of the Wnt signaling pathway; activates WNT3A signaling via DVL2.
HOATZ	Cilia- and flagella-associated protein HOATZ	Required for motile ciliogenesis and flagellar genesis by mediating the maturation of the glycolytic enzyme ENO4.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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
Enzyme (other)	1	2.4×	0.353
Other/Unknown	4	1.4×	0.353

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHD	Other/Unknown	no		CybS, SQR/QFR_C/D
TIMM8B	Other/Unknown	no		Tim10-like, Tim10-like_dom_sf
ALG9	Enzyme (other)	yes	2.4.1.259	GPI_mannosylTrfase
DIXDC1	Other/Unknown	no		DIX, CH_dom, Dsh/Dvl-rel
HOATZ	Other/Unknown	no		HOATZ-like

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
jejunum	1
rectum	1
cervix squamous epithelium	1
heart right ventricle	1
tongue squamous epithelium	1
body of pancreas	1
endothelial cell	1
ganglionic eminence	1
blood vessel layer	1
calcaneal tendon	1
inferior vagus X ganglion	1
bronchial epithelial cell	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
TIMM8B	288	ubiquitous	marker	tongue squamous epithelium, heart right ventricle, cervix squamous epithelium
ALG9	240	ubiquitous	marker	endothelial cell, body of pancreas, ganglionic eminence
DIXDC1	283	ubiquitous	marker	calcaneal tendon, blood vessel layer, inferior vagus X ganglion
HOATZ	129	tissue_specific	marker	right uterine tube, bronchial epithelial cell, olfactory segment of nasal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHD	2,229
HOATZ	1,818
TIMM8B	1,579
ALG9	1,167
DIXDC1	782

Intra-cohort edges

A	B	Sources
SDHD	TIMM8B	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SDHD	O14521	2
ALG9	Q9H6U8	2
DIXDC1	Q155Q3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TIMM8B	Q9Y5J9	93.60
HOATZ	Q6PI97	74.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ALG9 causes CDG-1l	1	3806.7×	0.003	ALG9
Diseases associated with N-glycosylation of proteins	1	211.5×	0.023	ALG9
Maturation of TCA enzymes and regulation of TCA cycle	1	190.3×	0.023	SDHD
Citric acid cycle (TCA cycle)	1	141.0×	0.023	SDHD
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	69.2×	0.037	ALG9
Mitochondrial protein import	1	56.0×	0.038	TIMM8B
Diseases of glycosylation	1	43.8×	0.042	ALG9
Respiratory electron transport	1	31.7×	0.051	SDHD
Diseases of metabolism	1	26.8×	0.053	ALG9
Asparagine N-linked glycosylation	1	20.0×	0.064	ALG9
Post-translational protein modification	1	6.4×	0.175	ALG9
Disease	1	4.4×	0.223	ALG9
Metabolism of proteins	1	4.1×	0.223	ALG9

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
regulation of catecholamine secretion	1	3370.4×	0.007	SDHD
forebrain ventricular zone progenitor cell division	1	1123.5×	0.010	DIXDC1
mitochondrial electron transport, succinate to ubiquinone	1	674.1×	0.011	SDHD
cerebral cortex radially oriented cell migration	1	337.0×	0.015	DIXDC1
modification of postsynaptic actin cytoskeleton	1	280.9×	0.015	DIXDC1
protein insertion into mitochondrial inner membrane	1	259.3×	0.015	TIMM8B
dolichol-linked oligosaccharide biosynthetic process	1	168.5×	0.019	ALG9
obsolete protein targeting to mitochondrion	1	116.2×	0.020	TIMM8B
axoneme assembly	1	108.7×	0.020	HOATZ
regulation of microtubule cytoskeleton organization	1	108.7×	0.020	DIXDC1
tricarboxylic acid cycle	1	102.1×	0.020	SDHD
positive regulation of Wnt signaling pathway	1	76.6×	0.025	DIXDC1
negative regulation of neuron differentiation	1	54.4×	0.029	DIXDC1
protein N-linked glycosylation	1	52.7×	0.029	ALG9
proton motive force-driven mitochondrial ATP synthesis	1	52.7×	0.029	SDHD
regulation of actin cytoskeleton organization	1	31.5×	0.044	DIXDC1
canonical Wnt signaling pathway	1	30.6×	0.044	DIXDC1
cellular response to hypoxia	1	24.2×	0.051	SDHD
flagellated sperm motility	1	23.4×	0.051	HOATZ
sensory perception of sound	1	20.2×	0.056	TIMM8B
cilium assembly	1	14.7×	0.072	HOATZ
protein transport	1	8.8×	0.114	TIMM8B
spermatogenesis	1	7.0×	0.134	HOATZ

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SDHD	0	0
TIMM8B	0	0
ALG9	0	0
DIXDC1	0	0
HOATZ	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG9	2.4.1.259, 2.4.1.261	dolichyl-P-Man:Man6GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase, dolichyl-P-Man:Man8GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase

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

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	ALG9
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	SDHD, TIMM8B, DIXDC1, HOATZ

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)
SDHD	0	—
TIMM8B	0	—
ALG9	0	—
DIXDC1	0	—
HOATZ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.