Hereditary pheochromocytoma-paraganglioma

disease

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Also known as familial pheochromocytoma-paragangliomahereditary paraganglioma-pheochromocytomahereditary paraganglioma-pheochromocytoma syndromeSDHx-related paraganglioma-pheochromocytoma

Summary

Hereditary pheochromocytoma-paraganglioma (MONDO:0017366) is a disease (an umbrella term covering 9 Mondo subtypes) caused by variants in MAX, SDHA, SDHAF2, and 3 other genes, with 19 cohort genes and 1 clinical trial. The dominant Reactome pathway is Citric acid cycle (TCA cycle) (7 cohort genes).

At a glance

Prevalence: 1-9 / 1 000 000 (Europe)
Causal genes: MAX (GenCC Definitive), SDHA (GenCC Definitive), SDHAF2 (GenCC Definitive), SDHB (GenCC Definitive) (+2 more)
Umbrella term: 9 Mondo subtypes
Cohort genes: 19
ClinVar variants: 2,543
Phenotypes (HPO): 41
Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.3	Worldwide	Not yet validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0002668	Paraganglioma	Very frequent (80-99%)
HP:0006737	Extraadrenal pheochromocytoma	Very frequent (80-99%)
HP:0006748	Adrenal pheochromocytoma	Very frequent (80-99%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000096	Glomerulosclerosis	Frequent (30-79%)
HP:0000740	Episodic paroxysmal anxiety	Frequent (30-79%)
HP:0001069	Episodic hyperhidrosis	Frequent (30-79%)
HP:0001095	Hypertensive retinopathy	Frequent (30-79%)
HP:0001342	Cerebral hemorrhage	Frequent (30-79%)
HP:0001618	Dysphonia	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002331	Recurrent paroxysmal headache	Frequent (30-79%)
HP:0002574	Episodic abdominal pain	Frequent (30-79%)
HP:0002640	Hypertension associated with pheochromocytoma	Frequent (30-79%)
HP:0002864	Paraganglioma of head and neck	Frequent (30-79%)
HP:0003072	Hypercalcemia	Frequent (30-79%)
HP:0003345	Elevated urinary norepinephrine	Frequent (30-79%)
HP:0003574	Positive regitine blocking test	Frequent (30-79%)
HP:0003639	Elevated urinary epinephrine	Frequent (30-79%)
HP:0008629	Pulsatile tinnitus	Frequent (30-79%)
HP:0010532	Paroxysmal vertigo	Frequent (30-79%)
HP:0011703	Sinus tachycardia	Frequent (30-79%)
HP:0011979	Elevated urinary dopamine	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0031284	Flushing	Frequent (30-79%)
HP:0100749	Chest pain	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000790	Hematuria	Occasional (5-29%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001293	Cranial nerve compression	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001605	Vocal cord paralysis	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0003528	Elevated calcitonin	Occasional (5-29%)
HP:0005584	Renal cell carcinoma	Occasional (5-29%)
HP:0009711	Retinal capillary hemangioma	Occasional (5-29%)
HP:0012222	Arachnoid hemangiomatosis	Occasional (5-29%)
HP:0025269	Panic attack	Occasional (5-29%)
HP:0000526	Aniridia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary pheochromocytoma-paraganglioma
Mondo ID	MONDO:0017366
OMIM	168000
Orphanet	29072
UMLS	C4274332
MedGen	895844
GARD	0011984
Is cancer (heuristic)	no

Also known as: familial pheochromocytoma-paraganglioma · hereditary paraganglioma-pheochromocytoma · hereditary paraganglioma-pheochromocytoma syndrome · hereditary pheochromocytoma-paraganglioma · SDHx-related paraganglioma-pheochromocytoma

Data availability: 2,543 ClinVar variants · 21 GenCC gene-disease records.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › hereditary pheochromocytoma-paraganglioma

Subtypes (9): pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma/paraganglioma syndrome 2, pheochromocytoma/paraganglioma syndrome 3, pheochromocytoma/paraganglioma syndrome 5, pheochromocytoma/paraganglioma syndrome 6, pheochromocytoma/paraganglioma syndrome 7, TMEM127-related tumor predisposition, MAX-related tumor predisposition

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:

259 uncertain significance, 216 likely benign, 36 conflicting classifications of pathogenicity, 26 benign/likely benign, 25 pathogenic, 21 pathogenic/likely pathogenic, 12 benign, 5 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
142764	NM_003000.3(SDHB):c.72+1G>T	LOC129929542	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069038	NM_017849.4(TMEM127):c.12del (p.Gly5fs)	LOC129934333	Pathogenic	criteria provided, multiple submitters, no conflicts
1070595	NM_017849.4(TMEM127):c.24del (p.Leu9fs)	LOC129934333	Pathogenic	criteria provided, single submitter
1451314	NM_017849.4(TMEM127):c.24_48del (p.Leu9fs)	LOC129934333	Pathogenic	criteria provided, single submitter
1452727	NM_017849.4(TMEM127):c.2T>A (p.Met1Lys)	LOC129934333	Pathogenic	criteria provided, multiple submitters, no conflicts
1075945	NM_002382.5(MAX):c.55C>T (p.Gln19Ter)	MAX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141678	NM_002382.5(MAX):c.233dup (p.Asn78fs)	MAX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1436106	NM_002382.5(MAX):c.205_206del (p.Glu69fs)	MAX	Pathogenic	criteria provided, single submitter
1454157	NM_002382.5(MAX):c.91del (p.Leu31fs)	MAX	Pathogenic	criteria provided, single submitter
1458939	NM_002382.5(MAX):c.295+1G>T	MAX	Pathogenic	criteria provided, multiple submitters, no conflicts
1067840	NC_000011.9:g.(?61205087)(61213543_?)del	SDHAF2	Pathogenic	criteria provided, single submitter
1068054	NM_017841.4(SDHAF2):c.37-2A>G	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069215	NM_017841.4(SDHAF2):c.124del (p.Asp42fs)	SDHAF2	Pathogenic	criteria provided, multiple submitters, no conflicts
1210770	NM_017841.4(SDHAF2):c.130C>T (p.Gln44Ter)	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441880	NM_017841.4(SDHAF2):c.216T>A (p.Tyr72Ter)	SDHAF2	Pathogenic	criteria provided, single submitter
1451128	NM_017841.4(SDHAF2):c.267del (p.Phe89fs)	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452374	NM_017841.4(SDHAF2):c.229_230del (p.Arg77fs)	SDHAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12778	NM_003000.3(SDHB):c.268C>T (p.Arg90Ter)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
12779	NM_003000.3(SDHB):c.590C>G (p.Pro197Arg)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12781	NM_003000.3(SDHB):c.725G>A (p.Arg242His)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12782	NM_003000.3(SDHB):c.716_719del (p.Ser239fs)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
12783	NM_003000.3(SDHB):c.79C>T (p.Arg27Ter)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
140773	NM_003000.3(SDHB):c.286+2T>A	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
142047	NM_003000.3(SDHB):c.575G>A (p.Cys192Tyr)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142111	NM_003000.3(SDHB):c.286G>A (p.Gly96Ser)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142637	NM_003000.3(SDHB):c.689G>A (p.Arg230His)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142763	NM_003000.3(SDHB):c.136C>T (p.Arg46Ter)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
143027	NM_003000.3(SDHB):c.203G>A (p.Cys68Tyr)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165180	NM_003000.3(SDHB):c.277T>C (p.Cys93Arg)	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704532	NM_003000.3(SDHB):c.305_315del (p.Ala102fs)	SDHB	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 149 · Orphanet: 61 · 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
EGLN1	Definitive	Autosomal dominant	EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition	8
MAX	Definitive	Autosomal dominant	pheochromocytoma	7
SDHA	Definitive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	20
SDHAF2	Definitive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	5
SDHB	Definitive	Autosomal dominant	pheochromocytoma/paraganglioma syndrome 4	16
SDHC	Definitive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	11
SDHD	Definitive	Autosomal dominant	pheochromocytoma/paraganglioma syndrome 1	16
VHL	Definitive	Autosomal dominant	pheochromocytoma	12
FH	Strong	Autosomal dominant	pheochromocytoma-paraganglioma	16
KIF1B	Moderate	Autosomal dominant	pheochromocytoma	10
DLST	Supportive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	4
MDH2	Supportive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	4
NF1	Supportive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	9
SLC25A11	Supportive	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	3
MEN1	Limited	Autosomal dominant	hereditary pheochromocytoma-paraganglioma	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
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
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
SDHAF2	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
DLST	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
MAX	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
MDH2	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma
SLC25A11	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
EGLN1	Orphanet:247511	Autosomal dominant secondary polycythemia
VHL	Orphanet:238557	Chuvash erythrocytosis
VHL	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
VHL	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
VHL	Orphanet:892	Von Hippel-Lindau disease
KIF1B	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
KIF1B	Orphanet:99946	Autosomal dominant Charcot-Marie-Tooth disease type 2A1
FH	Orphanet:24	Fumaric aciduria
FH	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
FH	Orphanet:523	Hereditary leiomyomatosis and renal cell cancer
MEN1	Orphanet:2965	Prolactinoma
MEN1	Orphanet:314786	Silent pituitary adenoma

Cohort genes → proteins

19 cohort genes, 18 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	19

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	gencc,clinvar
SDHB	HGNC:10681	ENSG00000117118	P21912	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	gencc,clinvar
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	gencc,clinvar
SDHAF2	HGNC:26034	ENSG00000167985	Q9NX18	Succinate dehydrogenase assembly factor 2, mitochondrial	gencc,clinvar
DLST	HGNC:2911	ENSG00000119689	P36957	Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial	gencc,clinvar
MAX	HGNC:6913	ENSG00000125952	P61244	Protein max	gencc,clinvar
MDH2	HGNC:6971	ENSG00000146701	P40926	Malate dehydrogenase, mitochondrial	gencc,clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	gencc,clinvar
SLC25A11	HGNC:10981	ENSG00000108528	Q02978	Mitochondrial 2-oxoglutarate/malate carrier protein	gencc
EGLN1	HGNC:1232	ENSG00000135766	Q9GZT9	Egl nine homolog 1	gencc
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	gencc
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	gencc
FH	HGNC:3700	ENSG00000091483	P07954	Fumarate hydratase, mitochondrial	gencc
MEN1	HGNC:7010	ENSG00000133895	O00255	Menin	gencc
DAGLA	HGNC:1165	ENSG00000134780	Q9Y4D2	Diacylglycerol lipase-alpha	clinvar
TMEM127	HGNC:26038	ENSG00000135956	O75204	Transmembrane protein 127	clinvar
DNMT3A	HGNC:2978	ENSG00000119772	Q9Y6K1	DNA (cytosine-5)-methyltransferase 3A	clinvar
MAX-AS1	HGNC:58293	ENSG00000259118		MAX antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) 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).
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).
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).
SDHAF2	Succinate dehydrogenase assembly factor 2, mitochondrial	Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transpor…
DLST	Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial	Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex.
MAX	Protein max	Transcription regulator.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
SLC25A11	Mitochondrial 2-oxoglutarate/malate carrier protein	Catalyzes the transport of 2-oxoglutarate (alpha-oxoglutarate) across the inner mitochondrial membrane in an electroneutral exchange for malate.
EGLN1	Egl nine homolog 1	Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins.
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
KIF1B	Kinesin-like protein KIF1B	Has a plus-end-directed microtubule motor activity and functions as a motor for transport of vesicles and organelles along microtubules.
FH	Fumarate hydratase, mitochondrial	Catalyzes the reversible stereospecific interconversion of fumarate to L-malate.
MEN1	Menin	Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates ‘Lys-4’ of histone H3 (H3K4).
DAGLA	Diacylglycerol lipase-alpha	Serine hydrolase that hydrolyzes arachidonic acid-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG).
TMEM127	Transmembrane protein 127	Controls cell proliferation acting as a negative regulator of TOR signaling pathway mediated by mTORC1.
DNMT3A	DNA (cytosine-5)-methyltransferase 3A	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.

Protein-family classification

Druggable: 9 · Difficult: 3 · Unknown: 7 · Druggable fraction: 0.47

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)	7	4.4×	0.003
Complement	1	14.1×	0.206
Transporter	1	4.1×	0.436
Scaffold/PPI	1	0.9×	0.827
Transcription factor	2	0.9×	0.827
Other/Unknown	7	0.7×	0.971

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
SDHB	Enzyme (other)	yes	1.3.5.1	2Fe-2S_ferredoxin-type, Succ_DH/fum_Rdtase_Fe-S, 2Fe2S_fd_BS
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
SDHAF2	Other/Unknown	no		SDH, SDHAF2, SDH_sf
DLST	Enzyme (other)	yes	1.2.1.105	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
MAX	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf
MDH2	Enzyme (other)	yes	1.1.1.37	Lactate/malate_DH_N, Malate_DH_AS, L-lactate/malate_DH
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
SLC25A11	Transporter	yes		MCP_transmembrane, MCP_dom_sf, Mito_Metabolite_Transporter
EGLN1	Transcription factor	no	1.14.11.2	Znf_MYND, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
KIF1B	Scaffold/PPI	no		FHA_dom, Kinesin_motor_dom, PH_domain
FH	Enzyme (other)	yes	4.2.1.2	Fumarate_lyase_fam, Fum_hydII, L-Aspartase-like
MEN1	Other/Unknown	no		Menin
DAGLA	Enzyme (other)	yes	3.1.1.116	Fungal_lipase-type, AB_hydrolase_fold, DAG_Lipase-Related
TMEM127	Other/Unknown	no		TMEM127, TMEM127_TM
DNMT3A	Complement	yes	2.1.1.37	PWWP_dom, C5_MeTfrase, C5_DNA_meth_AS
MAX-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

17 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)	19
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	4
monocyte	3
heart left ventricle	2
cardiac ventricle	2
islet of Langerhans	2
right adrenal gland	2
right adrenal gland cortex	2
granulocyte	2
leukocyte	2
mononuclear cell	2
body of tongue	2
heart right ventricle	2
adrenal tissue	2
mucosa of transverse colon	1
jejunal mucosa	1
jejunum	1
rectum	1
adenohypophysis	1
type B pancreatic cell	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
SDHB	293	ubiquitous	marker	heart left ventricle, cardiac ventricle, apex of heart
SDHC	134	ubiquitous	marker	islet of Langerhans, right adrenal gland cortex, right adrenal gland
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
SDHAF2	229	ubiquitous	marker	islet of Langerhans, adenohypophysis, granulocyte
DLST	283	ubiquitous	marker	apex of heart, right adrenal gland cortex, right adrenal gland
MAX	299	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
MDH2	301	ubiquitous	marker	body of tongue, heart right ventricle, type B pancreatic cell
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
SLC25A11	289	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, right atrium auricular region
EGLN1	214	ubiquitous	marker	gastrocnemius, muscle of leg, adrenal tissue
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
KIF1B	287	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus
FH	292	ubiquitous	marker	heart right ventricle, body of tongue, cardiac ventricle
MEN1	271	ubiquitous	marker	granulocyte, lower esophagus mucosa, right hemisphere of cerebellum
DAGLA	171	ubiquitous	yes	right frontal lobe, prefrontal cortex, Brodmann (1909) area 10
TMEM127	284	ubiquitous	marker	leukocyte, monocyte, blood
DNMT3A	223	ubiquitous	marker	sural nerve, ganglionic eminence, ventricular zone
MAX-AS1	129		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 47.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
MDH2	5,749
NF1	5,540
SDHB	5,471
SDHC	5,278
MEN1	5,226
DNMT3A	4,771
FH	3,709
DLST	3,692
VHL	3,522

Intra-cohort edges

A	B	Sources
DLST	FH	string_interaction
DLST	MDH2	intact, string_interaction
DLST	SLC25A11	intact
EGLN1	KIF1B	string_interaction
EGLN1	SDHAF2	string_interaction
EGLN1	TMEM127	string_interaction
EGLN1	VHL	biogrid_interaction, intact, string_interaction
FH	MDH2	string_interaction
FH	SDHA	string_interaction
FH	SDHAF2	string_interaction
FH	SDHB	string_interaction
FH	SDHD	string_interaction
KIF1B	NF1	string_interaction
KIF1B	SDHAF2	string_interaction
KIF1B	SDHB	string_interaction
KIF1B	SDHC	string_interaction
KIF1B	SDHD	string_interaction
KIF1B	TMEM127	string_interaction
MDH2	SDHA	biogrid_interaction, string_interaction
MDH2	SDHB	biogrid_interaction, string_interaction
MDH2	SLC25A11	string_interaction
MDH2	TMEM127	string_interaction
MEN1	SDHAF2	string_interaction
MEN1	TMEM127	string_interaction
NF1	SDHAF2	string_interaction
NF1	SDHB	string_interaction
NF1	SDHD	string_interaction
NF1	TMEM127	string_interaction
SDHA	SDHAF2	biogrid_interaction, intact, string_interaction
SDHA	SDHB	biogrid_interaction, intact, string_interaction
SDHA	SDHC	biogrid_interaction, string_interaction
SDHA	SDHD	string_interaction
SDHA	SLC25A11	string_interaction
SDHA	TMEM127	string_interaction
SDHAF2	SDHB	string_interaction
SDHAF2	SDHC	string_interaction
SDHAF2	SDHD	string_interaction
SDHAF2	SLC25A11	string_interaction
SDHAF2	TMEM127	string_interaction
SDHB	SDHC	string_interaction
SDHB	SDHD	biogrid_interaction, string_interaction
SDHB	TMEM127	string_interaction
SDHC	SDHD	biogrid_interaction, intact, string_interaction
SDHC	TMEM127	string_interaction
SDHD	SLC25A11	string_interaction
SDHD	TMEM127	string_interaction
SLC25A11	TMEM127	string_interaction

Structural data

PDB: 15 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142
MEN1	O00255	69
EGLN1	Q9GZT9	64
DNMT3A	Q9Y6K1	43
NF1	P21359	26
MAX	P61244	12
MDH2	P40926	7
FH	P07954	7
SDHB	P21912	6
SDHA	P31040	5
SDHC	Q99643	2
SDHD	O14521	2
SDHAF2	Q9NX18	2
DLST	P36957	1
KIF1B	O60333	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A11	Q02978	87.54
TMEM127	O75204	77.38
DAGLA	Q9Y4D2	63.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 79. Enrichment computed across 19 evidence-associated genes (17 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 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Citric acid cycle (TCA cycle)	7	174.2×	3e-13	SDHA, SDHB, SDHC, SDHD, SDHAF2, MDH2, FH
Maturation of TCA enzymes and regulation of TCA cycle	5	167.9×	2e-09	SDHA, SDHB, SDHC, SDHD, SDHAF2
Respiratory electron transport	6	33.6×	4e-07	SDHA, SDHB, SDHC, SDHD, MDH2, SLC25A11
Aerobic respiration and respiratory electron transport	6	31.2×	4e-07	SDHA, SDHB, SDHC, SDHAF2, MDH2, SLC25A11
Malate-aspartate shuttle	2	149.3×	0.001	MDH2, SLC25A11
Metabolism	6	4.1×	0.028	SDHA, SDHB, SDHC, SDHAF2, MDH2, SLC25A11
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	2	23.2×	0.037	EGLN1, VHL
OADH complex synthesizes glutaryl-CoA from 2-OA	1	223.9×	0.043	DLST
Replication of the SARS-CoV-1 genome	1	167.9×	0.043	VHL
Replication of the SARS-CoV-2 genome	1	167.9×	0.043	VHL
OGDH complex synthesizes succinyl-CoA from 2-OG	1	167.9×	0.043	DLST
Arachidonate production from DAG	1	134.3×	0.049	DAGLA
Glycine degradation	1	96.0×	0.055	DLST
RAS signaling downstream of NF1 loss-of-function variants	1	96.0×	0.055	NF1
Mitochondrial protein degradation	2	13.4×	0.055	MDH2, FH
Organic anion transport by SLC5/17/25 transporters	1	84.0×	0.059	SLC25A11
RHOBTB3 ATPase cycle	1	67.2×	0.069	VHL
Protein lipoylation	1	61.1×	0.071	DLST
SUMOylation of DNA methylation proteins	1	39.5×	0.104	DNMT3A
Transcription of E2F targets under negative control by DREAM complex	1	32.0×	0.122	MAX
G0 and Early G1	1	25.8×	0.143	MAX
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	21.7×	0.162	MEN1
RHO GTPases activate IQGAPs	1	20.4×	0.165	MEN1
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	18.2×	0.169	MEN1
SUMOylation of ubiquitinylation proteins	1	17.2×	0.169	VHL
Transcriptional Regulation by E2F6	1	17.2×	0.169	MAX
Cyclin E associated events during G1/S transition	1	16.8×	0.169	MAX
Cyclin A:Cdk2-associated events at S phase entry	1	15.6×	0.169	MAX
Formation of WDR5-containing histone-modifying complexes	1	15.6×	0.169	MEN1
Oncogenic MAPK signaling	1	14.6×	0.174	NF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 18 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tricarboxylic acid cycle	8	227.0×	8e-16	SDHA, SDHB, SDHC, SDHD, SDHAF2, DLST, MDH2, FH
mitochondrial electron transport, succinate to ubiquinone	5	936.2×	8e-14	SDHA, SDHB, SDHC, SDHD, SDHAF2
proton motive force-driven mitochondrial ATP synthesis	4	58.5×	4e-05	SDHA, SDHB, SDHC, SDHD
succinate metabolic process	2	374.5×	5e-04	SDHA, SDHB
cellular response to hypoxia	4	26.9×	5e-04	SDHD, EGLN1, VHL, DNMT3A
malate metabolic process	2	208.1×	0.001	MDH2, FH
malate-aspartate shuttle	2	208.1×	0.001	MDH2, SLC25A11
aerobic respiration	3	41.3×	0.001	SDHB, SDHC, MDH2
respiratory electron transport chain	2	93.6×	0.005	SDHA, SDHB
fumarate metabolic process	1	936.2×	0.014	FH
protein-FAD linkage	1	936.2×	0.014	SDHAF2
positive regulation of mast cell apoptotic process	1	936.2×	0.014	NF1
regulation of glial cell differentiation	1	936.2×	0.014	NF1
regulation of catecholamine secretion	1	936.2×	0.014	SDHD
observational learning	1	936.2×	0.014	NF1
regulation of angiogenesis	2	46.8×	0.014	NF1, EGLN1
neuroblast proliferation	2	40.7×	0.014	NF1, DAGLA
gluconeogenesis	2	36.0×	0.016	MDH2, SLC25A11
obsolete regulation of arginine metabolic process	1	468.1×	0.020	FH
gamma-aminobutyric acid secretion, neurotransmission	1	468.1×	0.020	NF1
negative regulation of hypoxia-inducible factor-1alpha signaling pathway	1	468.1×	0.020	EGLN1
Schwann cell proliferation	1	312.1×	0.020	NF1
forebrain astrocyte development	1	312.1×	0.020	NF1
obsolete L-lysine catabolic process to acetyl-CoA via L-saccharopine	1	312.1×	0.020	DLST
Schwann cell migration	1	312.1×	0.020	NF1
glutamate secretion, neurotransmission	1	312.1×	0.020	NF1
negative regulation of mast cell proliferation	1	312.1×	0.020	NF1
retrograde trans-synaptic signaling by endocannabinoid	1	312.1×	0.020	DAGLA
2-oxoglutarate decarboxylation to succinyl-CoA	1	312.1×	0.020	DLST
regulation protein catabolic process at postsynapse	1	312.1×	0.020	EGLN1

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 6 · Undrugged: 13

Druggability breadth: 13 of 19 evidence-associated genes (68%) 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
SDHA	LINEZOLID
MDH2	LEVOTHYROXINE
EGLN1	ROXADUSTAT
VHL	OSIMERTINIB
MEN1	LOPERAMIDE
DAGLA	ORLISTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MEN1	475	4
EGLN1	11	4
VHL	7	4
DAGLA	3	4
SDHA	1	4
MDH2	1	4
SDHB	0	0
SDHC	0	0
SDHD	0	0
SDHAF2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LINEZOLID	4	SDHA
LEVOTHYROXINE	4	MDH2, MEN1
ROXADUSTAT	4	EGLN1
DAPRODUSTAT	4	EGLN1
VADADUSTAT	4	EGLN1
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 9.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
EGLN1	211	Binding:211
DNMT3A	120	Binding:118, ADMET:1, Functional:1
MAX	97	Binding:97
MEN1	93	Binding:86, Functional:7
DAGLA	48	Binding:48
MDH2	28	Binding:28
SDHB	4	Binding:4
SDHA	3	Binding:3
DLST	1	Binding:1
SLC25A11	1	Binding:1
KIF1B	1	Binding:1
FH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SDHB	1.3.5.1	succinate dehydrogenase
SDHC	1.3.5.1	succinate dehydrogenase
DLST	1.2.1.105	2-oxoglutarate dehydrogenase system
MDH2	1.1.1.37	(S)-malate dehydrogenase (NAD+, oxaloacetate-forming)
EGLN1	1.14.11.2, 1.14.11.29	procollagen-proline 4-dioxygenase, hypoxia-inducible factor-proline dioxygenase
VHL	2.3.2.B13
FH	4.2.1.2	fumarate hydratase
DAGLA	3.1.1.116	sn-1-specific diacylglycerol lipase
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EGLN1	211
VHL	3,575
DNMT3A	120

Pharmacogenomics

Cohort genes with a PharmGKB record: 18; 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)
LINEZOLID	4	SDHA
LEVOTHYROXINE	4	MDH2, MEN1
ROXADUSTAT	4	EGLN1
DAPRODUSTAT	4	EGLN1
VADADUSTAT	4	EGLN1
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	SDHA, MDH2, EGLN1, VHL, MEN1, DAGLA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	5	SDHB, SDHC, DLST, FH, DNMT3A
D	Druggable family + AlphaFold only, no drug	1	SLC25A11
E	Difficult family or no structure, no drug	7	SDHD, SDHAF2, MAX, NF1, KIF1B, TMEM127, MAX-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SDHB	4	SDHA
SDHC	0	SDHA
SDHD	0	SDHA
SDHAF2	0	SDHA
SLC25A11	1	MDH2
DNMT3A	120	—
DLST	1	—
MAX	97	—
NF1	0	—
KIF1B	1	—
FH	1	—
TMEM127	0	—
MAX-AS1	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
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition

Cohort genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, DLST, MAX, MDH2, NF1, SLC25A11, EGLN1, VHL, KIF1B, FH, MEN1, DAGLA, TMEM127, DNMT3A, MAX-AS1