Pheochromocytoma

Summary

Pheochromocytoma (MONDO:0008233) is a disease caused by variants in MAX, RET, SDHB, and 3 other genes, with 17 cohort genes and 116 clinical trials. The dominant Reactome pathway is Maturation of TCA enzymes and regulation of TCA cycle (4 cohort genes). Top therapeutic interventions include phenoxybenzamine, doxazosin, and edotreotide gallium ga-68.

At a glance

• Causal genes: MAX (GenCC Definitive), RET (GenCC Definitive), SDHB (GenCC Definitive), SDHD (GenCC Definitive) (+2 more)
• Cohort genes: 17
• ClinVar variants: 2,859
• Clinical trials: 116

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pheochromocytoma
Mondo ID	MONDO:0008233
MeSH	D010673
OMIM	171300
DOID	DOID:0050771
ICD-11	13029801
UMLS	C0031511
MedGen	18419
GARD	0015105
Is cancer (heuristic)	no

Also known as: phaeochromocytoma · pheochromocytoma

Data availability: 2,859 ClinVar variants · 13 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › benign neoplasm › pheochromocytoma

Related subtypes (28): respiratory system benign neoplasm, benign reproductive system neoplasm, benign digestive system neoplasm, benign endocrine neoplasm, cardiovascular organ benign neoplasm, immune system organ benign neoplasm, thoracic benign neoplasm, musculoskeletal system benign neoplasm, nervous system benign neoplasm, peritoneal benign neoplasm, integumentary system benign neoplasm, benign mesothelioma, benign mesenchymoma, benign perivascular tumor, benign urinary system neoplasm, calcifying fibrous tumor, benign mastocytoma, benign neoplasm of oral cavity, benign neoplasm of neck, benign neoplasm of salivary gland, benign neoplasm of lip, benign neoplasm of floor of mouth, benign neoplasm of pharynx, benign neoplasm of buccal mucosa, benign chondrogenic neoplasm, benign epithelial neoplasm, benign phyllodes tumor, germ cell benign neoplasm

Subtypes (2): 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:

235 uncertain significance, 147 likely benign, 68 conflicting classifications of pathogenicity, 56 pathogenic, 52 benign/likely benign, 21 pathogenic/likely pathogenic, 16 likely pathogenic, 4 benign, 1 likely pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1319258	NM_003002.4(SDHD):c.49C>T (p.Arg17Ter)	LOC126861339	Pathogenic	criteria provided, multiple submitters, no conflicts
142764	NM_003000.3(SDHB):c.72+1G>T	LOC129929542	Pathogenic/Likely 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
13905	NM_020975.6(RET):c.1852T>G (p.Cys618Gly)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13908	NM_020975.6(RET):c.1900T>G (p.Cys634Gly)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13909	NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13910	NM_020975.6(RET):c.1901G>C (p.Cys634Ser)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13911	NM_020975.6(RET):c.1901G>T (p.Cys634Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13916	NM_020975.6(RET):c.1859G>A (p.Cys620Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13917	NM_020975.6(RET):c.1900T>C (p.Cys634Arg)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13918	NM_020975.6(RET):c.1902C>G (p.Cys634Trp)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13919	NM_020975.6(RET):c.2753T>C (p.Met918Thr)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13928	NM_020975.6(RET):c.1859G>T (p.Cys620Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13946	NM_020975.6(RET):c.2410G>T (p.Val804Leu)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13951	NM_020975.6(RET):c.2671T>G (p.Ser891Ala)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
1065988	NM_003000.3(SDHB):c.200+1G>C	SDHB	Pathogenic	criteria provided, single submitter
1066038	NM_003000.3(SDHB):c.424-2A>G	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066588	NM_003000.3(SDHB):c.557G>A (p.Cys186Tyr)	SDHB	Pathogenic	criteria provided, single submitter
1069440	NM_003000.3(SDHB):c.412del (p.Asp138fs)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1070347	NM_003000.3(SDHB):c.466del (p.Tyr156fs)	SDHB	Pathogenic	criteria provided, single submitter
1072115	NM_003000.3(SDHB):c.765+1G>A	SDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072823	NC_000001.10:g.(?17345376)(17345463_?)del	SDHB	Pathogenic	criteria provided, single submitter
1072824	NC_000001.10:g.(?17345376)(17371403_?)del	SDHB	Pathogenic	criteria provided, single submitter
1074491	NM_003000.3(SDHB):c.17_18insACTCTCCTTGAGGCGCCGGTTGC (p.Ala15fs)	SDHB	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
12785	NM_003000.3(SDHB):c.136C>G (p.Arg46Gly)	SDHB	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 82 · Orphanet: 54 · 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
MAX	Definitive	Autosomal dominant	pheochromocytoma	7
RET	Definitive	Autosomal dominant	pheochromocytoma	16
SDHB	Definitive	Autosomal dominant	pheochromocytoma/paraganglioma syndrome 4	16
SDHD	Definitive	Autosomal dominant	pheochromocytoma/paraganglioma syndrome 1	16
TMEM127	Definitive	Autosomal dominant	pheochromocytoma	5
VHL	Definitive	Autosomal dominant	pheochromocytoma	12
KIF1B	Moderate	Autosomal dominant	pheochromocytoma	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
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
TMEM127	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
TMEM127	Orphanet:404511	Clear cell papillary renal cell carcinoma
MAX	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome
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
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
ALG9	Orphanet:730	Autosomal dominant polycystic kidney disease
ALG9	Orphanet:79328	ALG9-CDG
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

Cohort genes → proteins

17 cohort genes, 15 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHB	HGNC:10681	ENSG00000117118	P21912	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	gencc,clinvar
SDHD	HGNC:10683	ENSG00000204370	O14521	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	gencc,clinvar
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	gencc,clinvar
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	gencc,clinvar
TMEM127	HGNC:26038	ENSG00000135956	O75204	Transmembrane protein 127	gencc,clinvar
MAX	HGNC:6913	ENSG00000125952	P61244	Protein max	gencc,clinvar
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	gencc,clinvar
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	clinvar
SDHC	HGNC:10682	ENSG00000143252	Q99643	Succinate dehydrogenase cytochrome b560 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
DUSP2	HGNC:3068	ENSG00000158050	Q05923	Dual specificity protein phosphatase 2	clinvar
CHURC1-FNTB	HGNC:42960	ENSG00000125954		CHURC1-FNTB readthrough	clinvar
MAX-AS1	HGNC:58293	ENSG00000259118		MAX antisense RNA 1	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
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).
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.
TMEM127	Transmembrane protein 127	Controls cell proliferation acting as a negative regulator of TOR signaling pathway mediated by mTORC1.
MAX	Protein max	Transcription regulator.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…
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).
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).
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.
DUSP2	Dual specificity protein phosphatase 2	Dephosphorylates both phosphorylated Thr and Tyr residues in MAPK1, and dephosphorylation of phosphotyrosine is slightly faster than that of phosphothreonine.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

Protein-family classification

Druggable: 6 · Difficult: 2 · Unknown: 9 · Druggable fraction: 0.35

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)	4	2.8×	0.286
Phosphatase	1	4.9×	0.553
Kinase	1	1.6×	0.825
Scaffold/PPI	1	1.0×	0.825
Other/Unknown	9	0.9×	0.825
Transcription factor	1	0.5×	0.889

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHB	Enzyme (other)	yes	1.3.5.1	2Fe-2S_ferredoxin-type, Succ_DH/fum_Rdtase_Fe-S, 2Fe2S_fd_BS
SDHD	Other/Unknown	no		CybS, SQR/QFR_C/D
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
TMEM127	Other/Unknown	no		TMEM127, TMEM127_TM
MAX	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
SDHC	Enzyme (other)	yes	1.3.5.1	SuccDH_FuR_B_TM-su, Succ_DH_cytb556, Succ_DH_cyt_bsu_CS
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
DUSP2	Phosphatase	yes	3.1.3.16	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, Rhodanese-like_dom
CHURC1-FNTB	Other/Unknown	no
MAX-AS1	Other/Unknown	no
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot

Expression context

Cohort genes with no expression data: 0.

15 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	3
apex of heart	2
heart left ventricle	2
mononuclear cell	2
leukocyte	2
calcaneal tendon	2
male germ line stem cell (sensu Vertebrata) in testis	2
cardiac ventricle	1
jejunal mucosa	1
jejunum	1
rectum	1
cortical plate	1
biceps brachii	1
medial globus pallidus	1
skeletal muscle tissue of rectus abdominis	1
blood	1
dorsal root ganglion	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHB	293	ubiquitous	marker	heart left ventricle, cardiac ventricle, apex of heart
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
KIF1B	287	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus
TMEM127	284	ubiquitous	marker	leukocyte, monocyte, blood
MAX	299	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
SDHC	134	ubiquitous	marker	islet of Langerhans, right adrenal gland cortex, right adrenal gland
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
DUSP2	209	ubiquitous	marker	seminal vesicle, granulocyte, lymph node
CHURC1-FNTB	131	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle, primordial germ cell in gonad
MAX-AS1	129		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, bone marrow cell
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 27.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
NF1	5,540
SDHB	5,471
SDHC	5,278
RET	4,203
VHL	3,522
KIF1B	2,257
SDHD	2,229
DUSP2	1,919
HOATZ	1,818

Intra-cohort edges

A	B	Sources
KIF1B	NF1	string_interaction
KIF1B	RET	string_interaction
KIF1B	SDHB	string_interaction
KIF1B	SDHC	string_interaction
KIF1B	SDHD	string_interaction
KIF1B	TMEM127	string_interaction
NF1	RET	string_interaction
NF1	SDHB	string_interaction
NF1	SDHD	string_interaction
NF1	TMEM127	string_interaction
RET	SDHB	string_interaction
RET	SDHC	string_interaction
RET	SDHD	string_interaction
RET	TMEM127	biogrid_interaction, string_interaction
SDHA	SDHB	biogrid_interaction, intact, string_interaction
SDHA	SDHC	biogrid_interaction, string_interaction
SDHA	SDHD	string_interaction
SDHA	TMEM127	string_interaction
SDHB	SDHC	string_interaction
SDHB	SDHD	biogrid_interaction, string_interaction
SDHB	TIMM8B	string_interaction
SDHB	TMEM127	string_interaction
SDHC	SDHD	biogrid_interaction, intact, string_interaction
SDHC	TIMM8B	string_interaction
SDHC	TMEM127	string_interaction
SDHD	TIMM8B	string_interaction
SDHD	TMEM127	string_interaction

Structural data

PDB: 12 · AlphaFold-only: 3 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142
RET	P07949	34
NF1	P21359	26
MAX	P61244	12
SDHB	P21912	6
SDHA	P31040	5
SDHD	O14521	2
SDHC	Q99643	2
ALG9	Q9H6U8	2
KIF1B	O60333	1
DIXDC1	Q155Q3	1
DUSP2	Q05923	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TIMM8B	Q9Y5J9	93.60
TMEM127	O75204	77.38
HOATZ	Q6PI97	74.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 57. Enrichment computed across 17 evidence-associated genes (12 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 12 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	4	190.3×	2e-07	SDHB, SDHD, SDHA, SDHC
Citric acid cycle (TCA cycle)	4	141.0×	3e-07	SDHB, SDHD, SDHA, SDHC
Respiratory electron transport	4	31.7×	1e-04	SDHB, SDHD, SDHA, SDHC
Aerobic respiration and respiratory electron transport	3	22.1×	0.004	SDHB, SDHA, SDHC
Defective ALG9 causes CDG-1l	1	951.7×	0.012	ALG9
Replication of the SARS-CoV-1 genome	1	237.9×	0.034	VHL
Replication of the SARS-CoV-2 genome	1	237.9×	0.034	VHL
RAS signaling downstream of NF1 loss-of-function variants	1	135.9×	0.052	NF1
RHOBTB3 ATPase cycle	1	95.2×	0.066	VHL
RAF-independent MAPK1/3 activation	1	52.9×	0.082	DUSP2
Diseases associated with N-glycosylation of proteins	1	52.9×	0.082	ALG9
Formation of the nephric duct	1	52.9×	0.082	RET
RAF/MAP kinase cascade	2	10.2×	0.082	RET, NF1
Transcription of E2F targets under negative control by DREAM complex	1	45.3×	0.085	MAX
NPAS4 regulates expression of target genes	1	41.4×	0.085	RET
Formation of the ureteric bud	1	41.4×	0.085	RET
G0 and Early G1	1	36.6×	0.091	MAX
SUMOylation of ubiquitinylation proteins	1	24.4×	0.112	VHL
Transcriptional Regulation by E2F6	1	24.4×	0.112	MAX
Cyclin E associated events during G1/S transition	1	23.8×	0.112	MAX
Negative regulation of MAPK pathway	1	22.1×	0.112	DUSP2
Cyclin A:Cdk2-associated events at S phase entry	1	22.1×	0.112	MAX
RET signaling	1	21.6×	0.112	RET
Oncogenic MAPK signaling	1	20.7×	0.112	NF1
G1/S Transition	1	19.4×	0.115	MAX
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	17.3×	0.120	ALG9
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	1	16.4×	0.120	VHL
Regulation of RAS by GAPs	1	16.1×	0.120	NF1
Mitotic G1 phase and G1/S transition	1	15.3×	0.120	MAX
S Phase	1	15.1×	0.120	MAX

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 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	4	898.8×	4e-10	SDHB, SDHD, SDHA, SDHC
tricarboxylic acid cycle	4	136.2×	2e-06	SDHB, SDHD, SDHA, SDHC
proton motive force-driven mitochondrial ATP synthesis	4	70.2×	2e-05	SDHB, SDHD, SDHA, SDHC
succinate metabolic process	2	449.4×	3e-04	SDHB, SDHA
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	2	204.3×	0.002	RET, NF1
respiratory electron transport chain	2	112.3×	0.004	SDHB, SDHA
positive regulation of mast cell apoptotic process	1	1123.5×	0.017	NF1
regulation of glial cell differentiation	1	1123.5×	0.017	NF1
regulation of catecholamine secretion	1	1123.5×	0.017	SDHD
observational learning	1	1123.5×	0.017	NF1
negative regulation of MAPK cascade	2	40.1×	0.019	DUSP2, NF1
embryonic epithelial tube formation	1	561.7×	0.021	RET
posterior midgut development	1	561.7×	0.021	RET
gamma-aminobutyric acid secretion, neurotransmission	1	561.7×	0.021	NF1
Schwann cell proliferation	1	374.5×	0.021	NF1
forebrain ventricular zone progenitor cell division	1	374.5×	0.021	DIXDC1
forebrain astrocyte development	1	374.5×	0.021	NF1
Schwann cell migration	1	374.5×	0.021	NF1
glutamate secretion, neurotransmission	1	374.5×	0.021	NF1
negative regulation of mast cell proliferation	1	374.5×	0.021	NF1
positive regulation of metanephric glomerulus development	1	374.5×	0.021	RET
negative regulation of Schwann cell migration	1	374.5×	0.021	NF1
vascular associated smooth muscle cell migration	1	374.5×	0.021	NF1
aerobic respiration	2	33.0×	0.021	SDHB, SDHC
mast cell apoptotic process	1	280.9×	0.022	NF1
negative regulation of Rac protein signal transduction	1	280.9×	0.022	NF1
ureter maturation	1	280.9×	0.022	RET
Peyer’s patch morphogenesis	1	280.9×	0.022	RET
myeloid leukocyte migration	1	280.9×	0.022	NF1
GDF15-GFRAL signaling pathway	1	280.9×	0.022	RET

Therapeutics

Drug target analysis

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

Druggability breadth: 7 of 17 evidence-associated genes (41%) 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
VHL	OSIMERTINIB
RET	PONATINIB
SDHA	LINEZOLID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
VHL	7	4
SDHA	1	4
DUSP2	1	2
SDHB	0	0
SDHD	0	0
KIF1B	0	0
TMEM127	0	0
MAX	0	0
SDHC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	VHL
BRIGATINIB	4	RET, VHL
CRIZOTINIB	4	RET, VHL
ADAGRASIB	4	VHL
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
RET	1,586	Binding:1573, Functional:10, ADMET:3
MAX	97	Binding:97
SDHB	4	Binding:4
SDHA	3	Binding:3
KIF1B	1	Binding:1
DUSP2	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SDHB	1.3.5.1	succinate dehydrogenase
VHL	2.3.2.B13
RET	2.7.10.1	receptor protein-tyrosine kinase
SDHC	1.3.5.1	succinate dehydrogenase
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
DUSP2	3.1.3.16	protein-serine/threonine phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
VHL	3,575
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

28 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)
OSIMERTINIB	4	VHL
BRIGATINIB	4	RET, VHL
CRIZOTINIB	4	RET, VHL
ADAGRASIB	4	VHL
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
NILOTINIB	4	RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	VHL, RET, SDHA
B	Phased (≥1) drug, not yet approved	1	DUSP2
C	Druggable family + PDB, no drug	3	SDHB, SDHC, ALG9
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	10	SDHD, KIF1B, TMEM127, MAX, TIMM8B, DIXDC1, HOATZ, CHURC1-FNTB, MAX-AS1, NF1

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
SDHD	0	SDHA
TMEM127	0	RET
SDHC	0	SDHA
KIF1B	1	—
MAX	97	—
TIMM8B	0	—
ALG9	0	—
DIXDC1	0	—
HOATZ	0	—
CHURC1-FNTB	0	—
MAX-AS1	0	—
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 116.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	60
PHASE2	29
PHASE1	9
PHASE1/PHASE2	7
PHASE3	5
PHASE4	3
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05702944	PHASE4	RECRUITING	The Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma
NCT01379898	PHASE4	COMPLETED	Phenoxybenzamine Versus Doxazosin in PCC Patients
NCT01959711	PHASE4	COMPLETED	Randomized Clinical Trial of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Laparoscopic Adrenalectomy
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00126412	PHASE3	COMPLETED	Meta-Iodobenzylguanidine (123I mIBG) Scintigraphy in Patients Being Evaluated for Phaeochromocytoma or Neuroblastoma
NCT01373736	PHASE3	UNKNOWN	123I-MIBG Scintigraphy in Patients Being Evaluated for Neuroendocrine Tumors
NCT03176693	PHASE3	COMPLETED	Preoperative Alpha Blockade for Pheochromocytoma
NCT00107289	PHASE2	RECRUITING	Iodine I 131 Metaiodobenzylguanidine in Treating Patients With Recurrent, Progressive, or Refractory Neuroblastoma or Malignant Pheochromocytoma or Paraganglioma
NCT03206060	PHASE2	RECRUITING	Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma
NCT03839498	PHASE2	ACTIVE_NOT_RECRUITING	Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma
NCT03946527	PHASE2	ACTIVE_NOT_RECRUITING	LAnreotide in Metastatic Pheochromocytoma / PARAganglioma (LAMPARA)
NCT04711135	PHASE2	ACTIVE_NOT_RECRUITING	Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs
NCT04924075	PHASE2	RECRUITING	Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)
NCT05636618	PHASE1/PHASE2	RECRUITING	Targeted Alpha-Particle Therapy for Advanced Somatostatin Receptor Type 2 (SSTR2) Positive Tumors
NCT05944237	PHASE1/PHASE2	RECRUITING	HTL0039732 in Participants With Advanced Solid Tumours
NCT06045260	PHASE2	RECRUITING	Receptor Radionuclide Therapy With 177Lu-DOTATOC
NCT06427798	PHASE1/PHASE2	RECRUITING	Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheochromocytoma/Paraganglioma Previously Treated With Systemic Targeted Radioligand Therapy
NCT06429397	PHASE2	NOT_YET_RECRUITING	Anlotinib Combined With Benmelstobart for Advanced Pheochromocytoma
NCT06503146	PHASE2	RECRUITING	18F-Fibroblast Activation Protein Inhibitor ([18F]FAPI-74) PET Imaging for Cancer Detection
NCT06607692	PHASE1/PHASE2	RECRUITING	Study in Children and Adolescents of 177Lu-DOTATATE (Lutathera®) Combined With the PARP Inhibitor Olaparib for the Treatment of Recurrent or Relapsed Solid Tumours Expressing Somatostatin Receptor (SSTR) (LuPARPed).
NCT06683846	PHASE2	RECRUITING	Ivonescimab in the Treatment of Multiple Advanced Tumors
NCT07167329	PHASE2	RECRUITING	Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial
NCT00002608	PHASE2	COMPLETED	Combination Chemotherapy and Tamoxifen in Treating Patients With Solid Tumors
NCT00028106	PHASE2	COMPLETED	131MIBG to Treat Malignant Pheochromocytoma
NCT00458952	PHASE1/PHASE2	COMPLETED	Phase 1 Study of Iobenguane (MIBG) I 131 in Patients With Malignant Pheochromocytoma/Paraganglioma
NCT00466856	PHASE2	TERMINATED	Internal Radiation Therapy in Treating Patients With Liver Metastases From Neuroendocrine Tumors
NCT00843037	PHASE2	COMPLETED	Study Of Sunitinib In Patients With Recurrent Paraganglioma/Pheochromocytoma
NCT00874614	PHASE2	UNKNOWN	A Study Evaluating Ultratrace Iobenguane I131 in Patients With Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma
NCT00923481	PHASE2	COMPLETED	A Broad Multi-histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-small Cell Lung, Head and Neck Hepatocellular and Renal Cell Carcinomas, and Pheochromocytoma and Thyroid Tumors (Multi-H…
NCT01152827	PHASE2	COMPLETED	RAD001 in Pheochromocytoma or Nonfunctioning Carcinoid
NCT01413503	PHASE2	COMPLETED	A Phase II Study of 131I- Metaiodobenzylguanidine (MIBG) for Treatment of Metastatic or Unresectable Pheochromocytoma and Related Tumors
NCT01635907	PHASE2	COMPLETED	Dovitinib in Neuroendocrine Tumors
NCT01967576	PHASE2	COMPLETED	Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
NCT03165721	PHASE2	TERMINATED	A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine (SGI-110), in Children and Adults With Wild Type GIST,Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer
NCT03923257	PHASE1/PHASE2	WITHDRAWN	Dosimetry Guided PRRT With 177Lu-DOTATATE in Children and Adolescents
NCT04187404	PHASE1/PHASE2	TERMINATED	A Novel Therapeutic Vaccine (EO2401) in Metastatic Adrenocortical Carcinoma, or Malignant Pheochromocytoma/Paraganglioma
NCT04276597	PHASE2	WITHDRAWN	Phase-II Study of Lu177DOTATOC in Adults With STTR(+)Pulmonary, Pheochromocytoma, Paraganglioma, Unknown Primary, Thymus NETs (PUTNET), or Any Other Non-.GEP-NET.
NCT04320589	PHASE2	COMPLETED	the Effect of Dexmedetomidine and Magnesium Sulfate in Open Resection of Pheochromocytoma
NCT04400474	PHASE2	COMPLETED	Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System. The CABATEN Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENOXYBENZAMINE	4	9
DOXAZOSIN	4	6
EDOTREOTIDE GALLIUM GA-68	4	4
IOBENGUANE I 131	4	3
AXITINIB	4	2
BELZUTIFAN	4	2
DOXORUBICIN HYDROCHLORIDE	4	2
FILGRASTIM	4	2
IFOSFAMIDE	4	2
LUTETIUM OXODOTREOTIDE LU-177	4	2
FOSTAMATINIB DISODIUM	4	1
INDIUM IN 111 PENTETREOTIDE	4	1
LANREOTIDE	4	1
OCTREOTIDE ACETATE	4	1
POTASSIUM IODIDE	4	1
TEMSIROLIMUS	4	1
VANDETANIB	4	1
FLORBENGUANE F18	3	3
CATEQUENTINIB	3	2
VATALANIB	3	2
BENMELSTOBART	3	1
DOVITINIB	3	1
GUADECITABINE	3	1
LUTETIUM LU177 EDOTREOTIDE	2	2
EDOTREOTIDE YTTRIUM Y-90	2	1
TIGOZERTINIB	2	1
IOBENGUANE I 123	1	1
CHEMBL3939307	0	2
CHEMBL275117	0	1
CHEMBL4517714	0	1