Pheochromocytoma/paraganglioma syndrome 3

Summary

Pheochromocytoma/paraganglioma syndrome 3 (MONDO:0011544) is a disease caused by SDHC (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: SDHC (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 747

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pheochromocytoma/paraganglioma syndrome 3
Mondo ID	MONDO:0011544
MeSH	C565335
OMIM	605373
DOID	DOID:0061218
UMLS	C1854336
MedGen	340200
GARD	0010545
Is cancer (heuristic)	no

Also known as: paraganglioma caused by mutation in SDHC · paragangliomas 3 · paragangliomas type 3 · PGL3 · pheochromocytoma/paraganglioma syndrome 3 · SDHC paraganglioma · SDHC-related hereditary paraganglioma-pheochromocytoma syndrome (paragangliomas 3) · SDHC-related tumor predisposition

Data availability: 747 ClinVar variants · 3 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 › pheochromocytoma/paraganglioma syndrome 3

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, generalized juvenile polyposis/juvenile polyposis coli, 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, 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

600 retrieved; paginated sample, class counts are floors:

245 uncertain significance, 168 likely benign, 60 benign/likely benign, 44 pathogenic, 36 conflicting classifications of pathogenicity, 18 benign, 16 likely pathogenic, 13 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
559476	Single allele		Pathogenic	criteria provided, single submitter
1040338	NC_000001.10:g.(?161293394)(161293470_?)del	SDHC	Pathogenic	criteria provided, single submitter
1069194	NM_003001.5(SDHC):c.250_251del (p.Leu84fs)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts
1072200	NM_003001.5(SDHC):c.278dup (p.Gly94fs)	SDHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072500	NM_003001.5(SDHC):c.124del (p.Trp42fs)	SDHC	Pathogenic	criteria provided, single submitter
1072825	NC_000001.10:g.(?161310374)(161310455_?)del	SDHC	Pathogenic	criteria provided, single submitter
1076621	NC_000001.10:g.(?161332109)(161332308_?)del	SDHC	Pathogenic	criteria provided, single submitter
1076622	NC_000001.10:g.(?161326457)(161332308_?)del	SDHC	Pathogenic	criteria provided, single submitter
135194	NM_003001.5(SDHC):c.148C>T (p.Arg50Cys)	SDHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1443862	NC_000001.10:g.(?161310374)(161332308_?)del	SDHC	Pathogenic	criteria provided, single submitter
1456907	NM_003001.5(SDHC):c.214del (p.Arg72fs)	SDHC	Pathogenic	criteria provided, single submitter
1722989	NM_003001.5(SDHC):c.78-2A>G	SDHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1744549	NM_003001.5(SDHC):c.118del (p.Arg40fs)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts
1767917	NM_003001.5(SDHC):c.97_98dup (p.Ala34fs)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts
183753	NM_003001.5(SDHC):c.397C>T (p.Arg133Ter)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts
185473	NM_003001.5(SDHC):c.78-1G>A	SDHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187084	NM_003001.5(SDHC):c.380A>G (p.His127Arg)	SDHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189841	NM_003001.5(SDHC):c.224G>A (p.Gly75Asp)	SDHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1999178	NM_003001.5(SDHC):c.21-1G>A	SDHC	Pathogenic	criteria provided, single submitter
2036254	NM_003001.5(SDHC):c.220dup (p.Thr74fs)	SDHC	Pathogenic	criteria provided, single submitter
2036721	NM_003001.5(SDHC):c.288dup (p.Glu97Ter)	SDHC	Pathogenic	criteria provided, single submitter
2055039	NM_003001.5(SDHC):c.1A>C (p.Met1Leu)	SDHC	Pathogenic	criteria provided, single submitter
239456	NM_003001.3(SDHC):c.406-?_*2318+?del	SDHC	Pathogenic	criteria provided, single submitter
2424599	NC_000001.10:g.(?161298176)(161298297_?)del	SDHC	Pathogenic	criteria provided, single submitter
2424601	NC_000001.10:g.(?161284158)(161284225_?)del	SDHC	Pathogenic	criteria provided, single submitter
2442320	NM_003001.5(SDHC):c.77+1G>C	SDHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2442323	NM_003001.5(SDHC):c.49del (p.His17fs)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts
2573281	NM_003001.5(SDHC):c.107_108del (p.Glu36fs)	SDHC	Pathogenic	criteria provided, single submitter
2573308	NM_003001.5(SDHC):c.177C>A (p.Tyr59Ter)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts
2637552	NM_003001.5(SDHC):c.248_251del (p.Ser83fs)	SDHC	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 11 · 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
SDHC	Definitive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHC	Orphanet:139411	Carney triad
SDHC	Orphanet:201	Cowden syndrome
SDHC	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHC	Orphanet:44890	Gastrointestinal stromal tumor
SDHC	Orphanet:97286	Carney-Stratakis syndrome
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

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
SDHC	HGNC:10682	ENSG00000143252	Q99643	Succinate dehydrogenase cytochrome b560 subunit, mitochondrial	gencc,clinvar
SDHD	HGNC:10683	ENSG00000204370	O14521	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	clinvar
CD1A	HGNC:1634	ENSG00000158477	P06126	T-cell surface glycoprotein CD1a	clinvar
ADAMTS4	HGNC:220	ENSG00000158859	O75173	A disintegrin and metalloproteinase with thrombospondin motifs 4	clinvar
CFAP126	HGNC:32325	ENSG00000188931	Q5VTH2	Protein Flattop	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHC	Succinate dehydrogenase cytochrome b560 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).
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).
CD1A	T-cell surface glycoprotein CD1a	Antigen-presenting protein that binds self and non-self lipid and glycolipid antigens and presents them to T-cell receptors on natural killer T-cells.
ADAMTS4	A disintegrin and metalloproteinase with thrombospondin motifs 4	Cleaves aggrecan, a cartilage proteoglycan, at the ‘392-Glu-|-Ala-393’ site and may be involved in its turnover.
CFAP126	Protein Flattop	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Protease	1	7.3×	0.320
Antibody/Immunoglobulin	1	5.8×	0.320
Enzyme (other)	1	2.4×	0.471
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHC	Enzyme (other)	yes	1.3.5.1	SuccDH_FuR_B_TM-su, Succ_DH_cytb556, Succ_DH_cyt_bsu_CS
SDHD	Other/Unknown	no		CybS, SQR/QFR_C/D
CD1A	Antibody/Immunoglobulin	yes		Ig_C1-set, Ig-like_dom, MHC_I-like_Ag-recog
ADAMTS4	Protease	yes		TSP1_rpt, Peptidase_M12B, ADAM_Cys-rich
CFAP126	Other/Unknown	no		Fltp

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
islet of Langerhans	1
right adrenal gland	1
right adrenal gland cortex	1
jejunal mucosa	1
jejunum	1
rectum	1
skin of hip	1
thymus	1
upper leg skin	1
left uterine tube	1
omental fat pad	1
peritoneum	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHC	134	ubiquitous	marker	islet of Langerhans, right adrenal gland cortex, right adrenal gland
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
CD1A	87	tissue_specific	marker	thymus, upper leg skin, skin of hip
ADAMTS4	156	broad	marker	left uterine tube, omental fat pad, peritoneum
CFAP126	178	broad	marker	right uterine tube, bronchial epithelial cell, bronchus

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHC	5,278
SDHD	2,229
CD1A	1,702
ADAMTS4	1,542
CFAP126	929

Intra-cohort edges

A	B	Sources
CFAP126	SDHC	string_interaction
SDHC	SDHD	biogrid_interaction, intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD1A	P06126	16
ADAMTS4	O75173	5
SDHC	Q99643	2
SDHD	O14521	2
CFAP126	Q5VTH2	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 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
Maturation of TCA enzymes and regulation of TCA cycle	2	285.5×	3e-04	SDHC, SDHD
Citric acid cycle (TCA cycle)	2	211.5×	3e-04	SDHC, SDHD
Respiratory electron transport	2	47.6×	0.004	SDHC, SDHD
Defective B3GALTL causes PpS	1	77.2×	0.050	ADAMTS4
O-glycosylation of TSR domain-containing proteins	1	75.1×	0.050	ADAMTS4
Diseases associated with O-glycosylation of proteins	1	53.9×	0.058	ADAMTS4
O-linked glycosylation	1	36.1×	0.071	ADAMTS4
Diseases of glycosylation	1	32.8×	0.071	ADAMTS4
Degradation of the extracellular matrix	1	29.4×	0.071	ADAMTS4
Aerobic respiration and respiratory electron transport	1	22.1×	0.077	SDHC
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	21.8×	0.077	CD1A
Diseases of metabolism	1	20.1×	0.077	ADAMTS4
Extracellular matrix organization	1	15.8×	0.090	ADAMTS4
Adaptive Immune System	1	7.5×	0.173	CD1A
Post-translational protein modification	1	4.8×	0.244	ADAMTS4
Disease	1	3.3×	0.302	ADAMTS4
Immune System	1	3.2×	0.302	CD1A
Metabolism of proteins	1	3.1×	0.302	ADAMTS4
Metabolism	1	2.9×	0.302	SDHC

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
mitochondrial electron transport, succinate to ubiquinone	2	1348.2×	1e-05	SDHC, SDHD
tricarboxylic acid cycle	2	204.3×	4e-04	SDHC, SDHD
proton motive force-driven mitochondrial ATP synthesis	2	105.3×	9e-04	SDHC, SDHD
regulation of catecholamine secretion	1	3370.4×	0.001	SDHD
proteoglycan catabolic process	1	1123.5×	0.003	ADAMTS4
antigen processing and presentation, endogenous lipid antigen via MHC class Ib	1	674.1×	0.005	CD1A
antigen processing and presentation, exogenous lipid antigen via MHC class Ib	1	481.5×	0.006	CD1A
cilium organization	1	120.4×	0.020	CFAP126
positive regulation of T cell mediated cytotoxicity	1	102.1×	0.021	CD1A
extracellular matrix disassembly	1	73.3×	0.026	ADAMTS4
aerobic respiration	1	49.6×	0.035	SDHC
skeletal system development	1	25.1×	0.053	ADAMTS4
extracellular matrix organization	1	24.4×	0.053	ADAMTS4
cellular response to hypoxia	1	24.2×	0.053	SDHD
flagellated sperm motility	1	23.4×	0.053	CFAP126
defense response to bacterium	1	21.6×	0.054	ADAMTS4
adaptive immune response	1	16.9×	0.065	CD1A
immune response	1	9.4×	0.107	CD1A
proteolysis	1	6.8×	0.138	ADAMTS4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADAMTS4	5	3
SDHC	0	0
SDHD	0	0
CD1A	0	0
CFAP126	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MARIMASTAT	3	ADAMTS4
EPIGALOCATECHIN GALLATE	3	ADAMTS4
LUTEOLIN	2	ADAMTS4
ILOMASTAT	2	ADAMTS4
ALDUMASTAT	2	ADAMTS4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADAMTS4	55	Binding:54, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SDHC	1.3.5.1	succinate dehydrogenase

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

5 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)
MARIMASTAT	3	ADAMTS4
EPIGALOCATECHIN GALLATE	3	ADAMTS4
LUTEOLIN	2	ADAMTS4
ILOMASTAT	2	ADAMTS4
ALDUMASTAT	2	ADAMTS4

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	1	ADAMTS4
C	Druggable family + PDB, no drug	2	SDHC, CD1A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SDHD, CFAP126

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)
SDHC	0	—
SDHD	0	—
CD1A	0	—
CFAP126	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.