SDHD

Summary

SDHD (succinate dehydrogenase complex subunit D, HGNC:10683) is a protein-coding gene on chromosome 11q23.1, encoding Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial (O14521). 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). It is a selective cancer dependency (DepMap: 66.1% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6392 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary pheochromocytoma-paraganglioma (Definitive, ClinGen) — +10 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 830 total — 98 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 215
• Cancer dependency (DepMap): dependent in 66.1% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003002

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10683
Approved symbol	SDHD
Name	succinate dehydrogenase complex subunit D
Location	11q23.1
Locus type	gene with protein product
Status	Approved
Aliases	cybS
Ensembl gene	ENSG00000204370
Ensembl biotype	protein_coding
OMIM	602690
Entrez	6392

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 6 nonsense_mediated_decay

ENST00000375549, ENST00000525291, ENST00000526592, ENST00000528021, ENST00000528048, ENST00000528182, ENST00000530923, ENST00000534010, ENST00000640554, ENST00000714087, ENST00000714090, ENST00000714091, ENST00000938877

RefSeq mRNA: 4 — MANE Select: NM_003002 NM_001276503, NM_001276504, NM_001276506, NM_003002

CCDS: CCDS31678, CCDS60958, CCDS60959, CCDS60960

Canonical transcript exons

ENST00000375549 — 4 exons

Exon	Start	End
ENSE00002169115	112086873	112086959
ENSE00003554863	112087857	112087973
ENSE00003636526	112088867	112089011
ENSE00004022763	112094805	112095794

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.8465 / max 243.7578, expressed in 1815 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116702	26.8465	1815

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.51	gold quality
rectum	UBERON:0001052	98.92	gold quality
jejunum	UBERON:0002115	98.91	gold quality
nephron tubule	UBERON:0001231	98.87	gold quality
biceps brachii	UBERON:0001507	98.83	gold quality
colonic mucosa	UBERON:0000317	98.78	gold quality
heart right ventricle	UBERON:0002080	98.76	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.74	gold quality
mucosa of transverse colon	UBERON:0004991	98.73	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.67	gold quality
adult organism	UBERON:0007023	98.62	gold quality
esophagus squamous epithelium	UBERON:0006920	98.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.56	gold quality
vastus lateralis	UBERON:0001379	98.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.51	gold quality
oral cavity	UBERON:0000167	98.50	gold quality
diaphragm	UBERON:0001103	98.50	gold quality
duodenum	UBERON:0002114	98.44	gold quality
gastrocnemius	UBERON:0001388	98.43	gold quality
body of tongue	UBERON:0011876	98.41	gold quality
adult mammalian kidney	UBERON:0000082	98.39	gold quality
transverse colon	UBERON:0001157	98.37	gold quality
muscle of leg	UBERON:0001383	98.32	gold quality
heart left ventricle	UBERON:0002084	98.30	gold quality
muscle organ	UBERON:0001630	98.28	gold quality
cardiac ventricle	UBERON:0002082	98.28	gold quality
right lobe of liver	UBERON:0001114	98.22	gold quality
quadriceps femoris	UBERON:0001377	98.21	gold quality
germinal epithelium of ovary	UBERON:0001304	98.20	gold quality
kidney epithelium	UBERON:0004819	98.15	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	7.77
E-MTAB-6058	no	370.37
E-MTAB-5061	no	3.27
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFYA

miRNA regulators (miRDB)

66 targeting SDHD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 66.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway (PMID:11605159)
• Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas (PMID:11897817)
• Alterations of the SDHD gene are involved in the tumorigenesis of both midgut carcinoids and Merkel cell carcinomas. (PMID:12007193)
• identification of novel mutations in patients with phaeochromocytoma and/or paraganglioma (PMID:12111639)
• Germ-line mutation in SDHD is associated with parasympathetic paraganglioma (PMID:12114404)
• Review. Succinate dehydrogenase catalyses a step in the Krebs tricarboxylic-acid cycle. Inherited heterozygous mutations in the gene encoding this enzyme causes a predisposition to inherited neoplasia syndromes. (PMID:12612654)
• Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family: a founder effect. (PMID:12782822)
• SDHD may have a role in colorectal and gastric cancers as a distinct type of tumor suppressor (PMID:12883710)
• Loss of chromosome 11 regions, including the deletion of PGL1 and PGL2 loci, may result in a severe phenotype, as exemplified by the development of paraganglioma. (PMID:15066320)
• germline mutation in the succinate dehydrogenase subunit D (SDHD) gene (PMID:15365827)
• Germline mutation on the SDHD gene was present in patients with pheochromocytoma or functional paraganglioma. (PMID:16314641)
• A possible role for SDH polymorphism as susceptibility/disease modifying factors in familial and sporadic medullary thyroid carcinomas was shown. (PMID:16322339)
• Pseudo-hypoxia can be observed in SDH-suppressed cells in the absence of oxidative stress and in the presence of effective antioxidant treatment. (PMID:16797480)
• prevalence of paragangliomas in carriers of D92Y mutations is at least 2.5%. (PMID:17227803)
• The genes most frequently implicated: SDHD and SDHB, also predispose to phaeochromocytoma. SDHD shows a complex inheritance pattern - tumours do not develop if the mutation is inherited from the mother. (PMID:17298303)
• Two novel SDH mutations in Japanese pheochromocytomas. (PMID:17308434)
• mutation not found in Chinese patients with sporadic pheochromocytoma/paraganglioma (PMID:17526943)
• study showed SDHD germ-line mutations are rare in patients with pheochromocytoma (PMID:17576205)
• investigated 11 patients with the dyad of ‘paraganglioma and gastric stromal sarcoma’; in eight, from 7 unrelated families, the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively) (PMID:17667967)
• Results describe copy number aberrations in the SDHD and MMP12 genes in an affected Solar Keratosis and control cohort. (PMID:17727250)
• familial gastrointestinal stromal tumors may be caused by mutations of the succinate dehydrogenase subunit genes SDHB, SDHC, and SDHD (PMID:17804857)
• Germline SDHD mutations underlying metastatic paraganglioma were G148D, Y114X, L85X, W43X, D92Y, and IVS2+5G–>A (PMID:17973943)
• Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. (PMID:18211978)
• SDHD mutation in sporadic head and neck paraganglioma (PMID:18561749)
• analysis of germline mutations and variants in the succinate dehydrogenase genes SDHB and SDHD in Cowden and Cowden-like syndromes (PMID:18678321)
• the SDHD p.Cys11X mutation is a founding mutation associated with a high penetrance for paraganglial tumors (PMID:18826997)
• Patients with SDHB mutations may present with biochemically silent abdominal paragangliomas due to defective catecholamine synthesis resulting from the absence of tyrosine hydroxylase (PMID:18840642)
• This case report highlights the variable expressivity of a single mutation in SDHD, (F933>X67), consistent with a diagnosis of hereditary paraganglioma syndromes. (PMID:19072999)
• mediastinal paragangliomas are strongly associated with SDHD gene mutations (PMID:19075037)
• We present the first reported case of a patient with a CPA tumor and a maternally inherited SDHD gene mutation. (PMID:19205158)
• Here we report a family with multiple cases of PGL which co-segregates with a novel SDHD gene mutation predictable to give rise to an abnormal gene product (CybS). (PMID:19239085)
• Mutations in SDHD-associated head-and-neck paragangliomas is also associated with pheochromocytomas and extra-adrenal paragangliomas. (PMID:19289533)
• Fifteen cases of PGL carried a germline mutation in SDHB or SDHD, four of which not described before. (PMID:19393419)
• Multiple genetic alterations including mutations, polymorphisms and intronic variants are more frequently observed in malignant pheochromocytomas. (PMID:19399650)
• Gene deletions of SDHD and SDHC represent a substantial proportion of all mutations, and must be considered in paraganglioma patients shown to be negative for mutations by sequencing. (PMID:19546167)
• Both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. (PMID:19584903)
• no clear association was found between gene variants involved in oxygen sensing and chemoresponsiveness, although some mutations in the SDHB and SDHD genes deserve further investigations in a larger population. (PMID:19768395)
• We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations for head and neck paragangliomas (HNPGL), adrenal pheochromocytoma and renal tumors. (PMID:19802898)
• These data describe a large SDHD deletion at the genomic sequence level and indicate that gross SDHD deletions could be a founder paraganglioma mutation in certain populations. (PMID:20111059)
• In patients with sporadic pheochromocytomas and paragangliomas, most frequent were mutations in RET proto-oncogene, followed by VHL gene, one mutation in SDHB, and one in SDHD genes. (PMID:20205103)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sdhdb	ENSDARG00000030139
danio_rerio	sdhda	ENSDARG00000055712
mus_musculus	Sdhd	ENSMUSG00000000171
rattus_norvegicus		ENSRNOG00000084067
drosophila_melanogaster	SdhD	FBGN0039112
caenorhabditis_elegans		WBGENE00009353

Protein

Protein identifiers

Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial — O14521 (reviewed: O14521)

Alternative names: CII-4, Malate dehydrogenase [quinone] cytochrome b small subunit, QPs3, Succinate dehydrogenase complex subunit D, Succinate-ubiquinone oxidoreductase cytochrome b small subunit, Succinate-ubiquinone reductase membrane anchor subunit

All UniProt accessions (10): O14521, A0A0S2Z4H7, A0A0S2Z4J3, A0A1W2PNY0, A0AAQ5BHF6, A0AAQ5BHH5, A0AAQ5BHI1, E9PK73, G3V173, H0YD96

UniProt curated annotations — full annotation on UniProt →

Function. 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). SDH also oxidizes malate to the non-canonical enol form of oxaloacetate, enol-oxaloacetate. Enol-oxaloacetate, which is a potent inhibitor of the succinate dehydrogenase activity, is further isomerized into keto-oxaloacetate.

Subunit / interactions. Component of complex II composed of four subunits: the flavoprotein (FP) SDHA, iron-sulfur protein (IP) SDHB, and a cytochrome b560 composed of SDHC and SDHD.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Pheochromocytoma/paraganglioma syndrome 1 (PPGL1) [MIM:168000] A form of pheochromocytoma/paraganglioma syndrome, a tumor predisposition syndrome characterized by the development of neuroendocrine tumors, usually in adulthood. Pheochromocytomas are catecholamine-producing tumors that arise from chromaffin cells in the adrenal medulla. Paragangliomas develop from sympathetic paraganglia in the thorax, abdomen, and pelvis, as well as from parasympathetic paraganglia in the head and neck. PPGL1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Paraganglioma and gastric stromal sarcoma (PGGSS) [MIM:606864] Gastrointestinal stromal tumors may be sporadic or inherited in an autosomal dominant manner, alone or as a component of a syndrome associated with other tumors, such as in the context of neurofibromatosis type 1 (NF1). Patients have both gastrointestinal stromal tumors and paragangliomas. Susceptibility to the tumors was inherited in an apparently autosomal dominant manner, with incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial complex II deficiency, nuclear type 3 (MC2DN3) [MIM:619167] A form of mitochondrial complex II deficiency, a disorder with heterogeneous clinical manifestations. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. MC2DN3 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Carbohydrate metabolism; tricarboxylic acid cycle.

Similarity. Belongs to the CybS family.

Isoforms (4)

UniProt ID	Names	Canonical?
O14521-1	1	yes
O14521-2	2
O14521-3	3
O14521-4	4

RefSeq proteins (4): NP_001263432, NP_001263433, NP_001263435, NP_002993* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007992	CybS	Family
IPR034804	SQR/QFR_C/D	Homologous_superfamily

Pfam: PF05328

UniProt features (33 total): sequence variant 12, helix 5, splice variant 4, topological domain 4, transmembrane region 3, binding site 2, transit peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9KC4	ELECTRON MICROSCOPY	2.65
8GS8	ELECTRON MICROSCOPY	2.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14521-F1	81.50	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 114; 102 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle

MSigDB gene sets: 647 (showing top): MODULE_93, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, MORF_HDAC1, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOLDRATH_ANTIGEN_RESPONSE, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, GOBP_ATP_BIOSYNTHETIC_PROCESS

GO Biological Process (5): tricarboxylic acid cycle (GO:0006099), mitochondrial electron transport, succinate to ubiquinone (GO:0006121), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), regulation of catecholamine secretion (GO:0050433), cellular response to hypoxia (GO:0071456)

GO Molecular Function (6): succinate dehydrogenase (quinone) activity (GO:0008177), electron transfer activity (GO:0009055), heme binding (GO:0020037), metal ion binding (GO:0046872), ubiquinone binding (GO:0048039), protein binding (GO:0005515)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial envelope (GO:0005740), mitochondrial inner membrane (GO:0005743), respiratory chain complex II (succinate dehydrogenase) (GO:0045273), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	2
Citric acid cycle (TCA cycle)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
aerobic respiration	1
primary metabolic process	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
catecholamine secretion	1
regulation of amine transport	1
regulation of secretion by cell	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
succinate dehydrogenase activity	1
oxidoreductase activity, acting on the CH-CH group of donors, quinone or related compound as acceptor	1
molecular_function	1
tetrapyrrole binding	1
cation binding	1
quinone binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle envelope	1
organelle inner membrane	1
mitochondrial membrane	1
membrane protein complex	1
respiratory chain complex	1
oxidoreductase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2188 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SDHD	SDHA	P31040	999
SDHD	SDHAF2	Q9NX18	999
SDHD	SDHC	Q99643	999
SDHD	SDHB	P21912	999
SDHD	F5H5T6	F5H5T6	994
SDHD	TMEM127	O75204	960
SDHD	SDHAF1	A6NFY7	940
SDHD	RET	P07949	904
SDHD	MT-CYB	P00156	871
SDHD	TIMM8B	Q9Y5J9	871
SDHD	NF1	P21359	835
SDHD	FH	P07954	776
SDHD	TIMM8A	O60220	763
SDHD	PDGFRA	P16234	735
SDHD	KIF1B	O60333	711

IntAct

19 interactions, top by confidence:

A	B	Type	Score
SDHD	RHBDD2	psi-mi:“MI:0915”(physical association)	0.560
MTNR1B	SDHD	psi-mi:“MI:0915”(physical association)	0.370
SDHD	F2RL1	psi-mi:“MI:0915”(physical association)	0.370
SDHD	GPR35	psi-mi:“MI:0915”(physical association)	0.370
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
SDHD	TNNC2	psi-mi:“MI:0914”(association)	0.350
SDHD	HBB	psi-mi:“MI:0914”(association)	0.350
SLC25A5		psi-mi:“MI:0914”(association)	0.350
AKT1	SDHD	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	SDHD	psi-mi:“MI:2364”(proximity)	0.270
SDHD	FBXW7	psi-mi:“MI:2364”(proximity)	0.270
SDHD	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SDHD	PTEN	psi-mi:“MI:2364”(proximity)	0.270
SDHD	RHBDD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): SDHD (Affinity Capture-MS), SDHD (Two-hybrid), SDHD (PCA), SDHD (Two-hybrid), SDHD (Two-hybrid), SDHD (Two-hybrid), PPIL3 (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), TBC1D24 (Affinity Capture-MS), DHODH (Affinity Capture-MS), IL17F (Affinity Capture-MS), SRC (Affinity Capture-MS), TNNC2 (Affinity Capture-MS), SDHB (Affinity Capture-MS), SDHC (Affinity Capture-MS)

ESM2 similar proteins: A5GZW8, A6H773, A6QPI4, D3ZAW2, O14521, O75208, P09925, Q05B67, Q08BI9, Q12887, Q15070, Q15526, Q2KHV4, Q2NL34, Q3B8P0, Q3SYV3, Q3TD49, Q4KLZ1, Q5EA03, Q5G2C6, Q5PQL3, Q5R460, Q5R5H4, Q5R7D0, Q5RC29, Q5RE99, Q5T6X4, Q5XIJ4, Q5XJY4, Q5ZIS0, Q5ZLJ4, Q68FN7, Q68FT1, Q6AZR3, Q6AZV0, Q6DGM2, Q6P355, Q6PCT8, Q800L1, Q8BSF4

Diamond homologs: A5GZW8, A8WT26, O14521, O62215, P92507, Q5G2C6, Q5RC29, Q5ZIS0, Q68FN7, Q6AZR3, Q6AZV0, Q6DGM2, Q6P355, Q6PCT8, Q7SGY6, Q8WSR2, Q95123, Q9CXV1, Q9VCI5, Q9P7X0, Q750S6, P37298

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
STOML2	“up-regulates activity”	SDHD
SDHD	“form complex”	“Succinate dehydrogenase-Mitochondrial respiratory chain complex II”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

830 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	98
Likely pathogenic	34
Uncertain significance	385
Likely benign	155
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076624	NC_000011.9:g.(?111957547)(111958707_?)del	Pathogenic
1372650	NM_003002.4(SDHD):c.281_282insAATA (p.Leu95fs)	Pathogenic
1381354	NC_000011.9:g.(?111957632)(111965694_?)del	Pathogenic
142068	NM_003002.4(SDHD):c.155C>A (p.Ser52Ter)	Pathogenic
1430410	NM_003002.4(SDHD):c.288del (p.Ala97fs)	Pathogenic
1453077	NM_003002.4(SDHD):c.169+1G>T	Pathogenic
1455596	NM_003002.4(SDHD):c.169+1G>A	Pathogenic
1457320	NM_003002.4(SDHD):c.224del (p.Leu75fs)	Pathogenic
1458129	NC_000011.9:g.(?111959581)(111965694_?)del	Pathogenic
1704646	GRCh37/hg19 11p13-q25(chr11:32799481-134938470)x3	Pathogenic
1728082	NM_003002.4(SDHD):c.314+1G>C	Pathogenic
1731167	NM_003002.4(SDHD):c.341_342del (p.Tyr114fs)	Pathogenic
1733584	NM_003002.4(SDHD):c.364A>T (p.Lys122Ter)	Pathogenic
1765433	NM_003002.4(SDHD):c.90_96del (p.His30fs)	Pathogenic
1794440	NM_003002.4(SDHD):c.266_267dup (p.Ala90fs)	Pathogenic
180590	NM_003002.4(SDHD):c.275A>G (p.Asp92Gly)	Pathogenic
186590	NM_003002.4(SDHD):c.298_301del (p.Thr100fs)	Pathogenic
1917924	NM_003002.4(SDHD):c.15G>A (p.Trp5Ter)	Pathogenic
2035265	NM_003002.4(SDHD):c.136_143del (p.Val46fs)	Pathogenic
2084230	NM_003002.4(SDHD):c.264C>A (p.Cys88Ter)	Pathogenic
2226832	NM_003002.4(SDHD):c.198G>A (p.Trp66Ter)	Pathogenic
239461	NM_003002.4(SDHD):c.173del (p.Gly58fs)	Pathogenic
239464	NM_003002.4(SDHD):c.242del (p.Pro81fs)	Pathogenic
2424602	NC_000011.9:g.(?111171709)(111959745_?)del	Pathogenic
2452939	NM_003002.4(SDHD):c.124G>T (p.Glu42Ter)	Pathogenic
2497774	NM_003002.4(SDHD):c.314+3A>T	Pathogenic
2567229	NM_003002.4(SDHD):c.69del (p.Pro24fs)	Pathogenic
2567231	NM_003002.4(SDHD):c.286del (p.Ala96fs)	Pathogenic
2575967	NM_003002.4(SDHD):c.295del (p.Leu99fs)	Pathogenic
2662026	NM_003002.4(SDHD):c.197G>A (p.Trp66Ter)	Pathogenic

SpliceAI

1003 predictions. Top by Δscore:

Variant	Effect	Δscore
11:112086922:GAGGC:G	donor_gain	1.0000
11:112086925:GC:G	donor_gain	1.0000
11:112086926:C:G	donor_gain	0.9900
11:112094803:A:AG	acceptor_gain	0.9900
11:112094803:AG:A	acceptor_gain	0.9900
11:112094804:G:GG	acceptor_gain	0.9900
11:112094804:GG:G	acceptor_gain	0.9900
11:112094867:C:T	donor_gain	0.9900
11:112094961:G:GT	donor_gain	0.9900
11:112095050:G:GT	donor_gain	0.9900
11:112086902:A:T	donor_gain	0.9800
11:112087974:G:GG	donor_gain	0.9800
11:112094799:CTTTA:C	acceptor_loss	0.9800
11:112094800:TTTA:T	acceptor_loss	0.9800
11:112094801:TTAG:T	acceptor_loss	0.9800
11:112094802:TA:T	acceptor_loss	0.9800
11:112094803:A:T	acceptor_loss	0.9800
11:112094803:AGG:A	acceptor_gain	0.9800
11:112094804:G:GA	acceptor_loss	0.9800
11:112094804:GGG:G	acceptor_gain	0.9800
11:112087518:A:T	donor_gain	0.9700
11:112118927:G:GT	donor_gain	0.9700
11:112095063:A:G	donor_gain	0.9600
11:112086901:G:GT	donor_gain	0.9500
11:112086958:AG:A	donor_loss	0.9500
11:112086959:GG:G	donor_loss	0.9500
11:112086960:GTGAG:G	donor_loss	0.9500
11:112088866:GCT:G	acceptor_gain	0.9500
11:112086951:G:GT	donor_gain	0.9400
11:112091468:GGC:G	donor_gain	0.9400

AlphaMissense

1006 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:112088914:A:C	S73R	0.989
11:112088916:T:A	S73R	0.989
11:112088916:T:G	S73R	0.989
11:112094919:C:A	N143K	0.985
11:112094919:C:G	N143K	0.985
11:112088971:G:C	D92H	0.983
11:112094933:G:T	G148V	0.975
11:112088984:C:A	A96D	0.974
11:112094908:T:C	C140R	0.974
11:112094903:G:A	G138E	0.972
11:112094932:G:C	G148R	0.972
11:112094902:G:A	G138R	0.971
11:112094902:G:C	G138R	0.971
11:112094959:T:A	W157R	0.971
11:112094959:T:C	W157R	0.971
11:112094915:T:C	F142S	0.970
11:112094936:T:A	I149N	0.970
11:112088945:C:A	A83D	0.968
11:112094948:T:A	V153D	0.967
11:112088987:C:A	A97E	0.966
11:112088895:G:C	W66C	0.965
11:112088895:G:T	W66C	0.965
11:112088907:G:C	R70S	0.963
11:112088907:G:T	R70S	0.963
11:112094927:A:T	D146V	0.963
11:112088903:A:T	E69V	0.962
11:112094906:T:C	L139P	0.962
11:112094944:G:C	A152P	0.962
11:112088929:G:C	G78R	0.961
11:112088972:A:T	D92V	0.961

dbSNP variants (sampled 300 via entrez): RS1000139770 (11:112090412 A>C), RS1000200403 (11:112092464 A>G), RS1000545537 (11:112088580 C>G), RS1000652803 (11:112095141 A>C), RS1001139895 (11:112088764 A>G), RS1001335553 (11:112089669 A>C), RS1001883229 (11:112085144 CTT>C), RS1002020406 (11:112084889 A>C), RS1002039990 (11:112092079 ACT>A), RS1002264692 (11:112094258 T>C), RS1002274236 (11:112088515 C>A,T), RS1002347725 (11:112088348 C>G,T), RS1002863066 (11:112092863 T>C), RS1003091519 (11:112090149 C>G), RS1003320468 (11:112087121 A>C)

Disease associations

OMIM: gene MIM:602690 | disease phenotypes: MIM:171300, MIM:606864, MIM:615106, MIM:168000, MIM:619167, MIM:252011, MIM:605373, MIM:158350, MIM:115310, MIM:114900

GenCC curated gene-disease

Disease	Classification	Inheritance
pheochromocytoma/paraganglioma syndrome 1	Definitive	Autosomal dominant
hereditary pheochromocytoma-paraganglioma	Definitive	Autosomal dominant
pheochromocytoma	Definitive	Autosomal dominant
Carney-Stratakis syndrome	Strong	Autosomal dominant
mitochondrial complex II deficiency, nuclear type 1	Strong	Autosomal recessive
mitochondrial complex 2 deficiency, nuclear type 3	Moderate	Autosomal recessive
mitochondrial complex II deficiency	Moderate	Autosomal recessive
renal cell carcinoma	Moderate	Autosomal dominant
Cowden disease	Supportive	Autosomal dominant
intestinal cancer	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Limited	AR
hereditary pheochromocytoma-paraganglioma	Definitive	AD

Mondo (17): pheochromocytoma (MONDO:0008233), Carney-Stratakis syndrome (MONDO:0011740), Cowden syndrome 3 (MONDO:0014045), hereditary neoplastic syndrome (MONDO:0015356), pheochromocytoma/paraganglioma syndrome 1 (MONDO:0008192), hereditary pheochromocytoma-paraganglioma (MONDO:0017366), mitochondrial complex 2 deficiency, nuclear type 3 (MONDO:0030937), mitochondrial complex II deficiency, nuclear type 1 (MONDO:0100294), paraganglioma (MONDO:0000448), pheochromocytoma/paraganglioma syndrome 3 (MONDO:0011544), Cowden disease (MONDO:0016063), microcephaly (MONDO:0001149), pheochromocytoma/paraganglioma syndrome 4 (MONDO:0007273), intestinal neuroendocrine tumor G1 (MONDO:0021533), (MONDO:0009641)

Orphanet (5): Cowden syndrome (Orphanet:201), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Carney-Stratakis syndrome (Orphanet:97286), Inherited cancer-predisposing syndrome (Orphanet:140162), Isolated succinate-CoQ reductase deficiency (Orphanet:3208)

HPO phenotypes

215 total (30 of 215 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000036	Abnormal penis morphology
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000130	Abnormality of the uterus
HP:0000158	Macroglossia
HP:0000218	High palate
HP:0000221	Furrowed tongue
HP:0000256	Macrocephaly
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0000405	Conductive hearing impairment
HP:0000478	Abnormality of the eye
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000526	Aniridia
HP:0000543	Optic disc pallor
HP:0000544	External ophthalmoplegia
HP:0000545	Myopia
HP:0000580	Pigmentary retinopathy
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000717	Autism
HP:0000726	Dementia
HP:0000737	Irritability
HP:0000740	Episodic paroxysmal anxiety
HP:0000767	Pectus excavatum

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007325_232	General risk tolerance (MTAG)	4.000000e-09
GCST010703_266	Brain morphology (MOSTest)	4.000000e-13
GCST90020029_250	Waist circumference adjusted for body mass index	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D002292	Carcinoma, Renal Cell	C04.557.470.200.025.390; C04.588.945.947.535.160; C12.050.351.937.820.535.160; C12.050.351.968.419.473.160; C12.200.758.820.750.160; C12.200.777.419.473.160; C12.900.820.535.160; C12.950.419.473.160; C12.950.983.535.160
D006223	Hamartoma Syndrome, Multiple	C04.445.435; C04.651.435; C04.700.435; C16.320.700.435
D007414	Intestinal Neoplasms	C04.588.274.476.411; C06.301.371.411; C06.405.249.411; C06.405.469.491
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010235	Paraganglioma	C04.557.465.625.650.700; C04.557.580.625.650.700
D010673	Pheochromocytoma	C04.557.465.625.650.700.725; C04.557.580.625.650.700.725
C562842	Carcinoid Tumors, Intestinal (supp.)
C564650	Carney-Stratakis Syndrome (supp.)
C565375	Mitochondrial Complex II Deficiency (supp.)
C565335	Paragangliomas 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	decreases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
4-chlorobiphenyl	decreases expression	1
arsenite	affects binding, increases reaction	1
2,6-dichloro-4-nitrophenol	decreases expression	1
sodium arsenite	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
bisphenol AF	decreases expression	1
Atrazine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Fluorouracil	affects expression	1
Indomethacin	decreases expression, affects cotreatment	1
Ozone	affects expression, increases abundance	1
Thiram	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Zidovudine	increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3GL	Abcam HEK293T SDHD KO	Transformed cell line	Female

Clinical trials (associated diseases)

415 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00414765	PHASE4	COMPLETED	Aldesleukin in Participants With Metastatic Renal Cell Carcinoma or Metastatic Melanoma
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT00930345	PHASE4	TERMINATED	Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma
NCT01206764	PHASE4	COMPLETED	A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.
NCT01266837	PHASE4	COMPLETED	Open Label, Single Arm Trial to Characterize Patients With Metastatic RCC Treated With Everolimus After Failure of the First VEGF-targeted Therapy (MARC-2)
NCT02056587	PHASE4	COMPLETED	Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
NCT02338570	PHASE4	TERMINATED	Outcome-related Factors in Patients With Metastatic Renal Cell Carcinoma Treated With Everolimus (ORCHIDEE)
NCT02596035	PHASE4	COMPLETED	An Investigational Immuno-therapy Safety Trial of Nivolumab in Patients With Advanced or Metastatic Renal Cell Carcinoma
NCT02982954	PHASE4	COMPLETED	A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT07028125	PHASE4	RECRUITING	Digital Monitoring of Self-reported Symptoms by Patients Treated With Cabozantinib Plus Nivolumab for Advanced Clear-cell Renal Carcinoma
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT01379898	PHASE4	COMPLETED	Phenoxybenzamine Versus Doxazosin in PCC Patients
NCT01959711	PHASE4	COMPLETED	Randomized Clinical Trial of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Laparoscopic Adrenalectomy
NCT05702944	PHASE4	RECRUITING	The Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma
NCT00033904	PHASE3	COMPLETED	Survival Study Of Oncophage® vs. Observation In Patients With Kidney Cancer
NCT00126178	PHASE3	TERMINATED	Clinical Trial Studying a Personalized Cancer Vaccine in Patients With Non-metastatic Kidney Cancer
NCT00291369	PHASE3	COMPLETED	Cytokines in Patients With Metastatic Renal Cell Carcinoma of Intermediate Prognosis
NCT00410124	PHASE3	COMPLETED	RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib
NCT00474786	PHASE3	COMPLETED	Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib
NCT00478114	PHASE3	COMPLETED	Efficacy and Safety of Sorafenib in Advanced Renal Cell Carcinoma (RCC)
NCT00606632	PHASE3	COMPLETED	Pre-surgical Detection of Clear Cell Renal Cell Carcinoma (ccRCC) Using Radiolabeled G250-Antibody
NCT00606866	PHASE3	COMPLETED	MRI Study of BAY 43-9006 in Metastatic Renal Cell Carcinoma
NCT00631371	PHASE3	COMPLETED	Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects
NCT00732914	PHASE3	COMPLETED	Sequential Study to Treat Renal Cell Carcinoma
NCT00869011	PHASE3	UNKNOWN	Exercise for Patients With Renal Cell Cancer Receiving Sunitinib
NCT00930033	PHASE3	COMPLETED	Clinical Trial to Assess the Importance of Nephrectomy
NCT01030783	PHASE3	COMPLETED	A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma
NCT01076010	PHASE3	COMPLETED	An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301).
NCT01198158	PHASE3	TERMINATED	Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy
NCT01223027	PHASE3	COMPLETED	Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma
NCT01224288	PHASE3	ACTIVE_NOT_RECRUITING	Dynamic Contrast Enhancement Computed Tomography for Evaluating Tumor Perfusion in Patients With Metastatic Renal Cell Carcinoma Receiving Targeted Therapies: Renal Cell Carcinoma (RCC) Scramble
NCT01235962	PHASE3	COMPLETED	A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC)
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01265901	PHASE3	COMPLETED	IMA901 in Patients Receiving Sunitinib for Advanced/Metastatic Renal Cell Carcinoma
NCT01481870	PHASE3	UNKNOWN	Comparison of Sequential Therapies With Sunitinib and Sorafenib in Advanced Renal Cell Carcinoma
NCT01582672	PHASE3	TERMINATED	Phase 3 Trial of Autologous Dendritic Cell Immunotherapy Plus Standard Treatment of Advanced Renal Cell Carcinoma
NCT01613846	PHASE3	COMPLETED	Phase III Sequential Open-label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Pazopanib Versus Pazopanib Followed by Sorafenib in the Treatment of Advanced / Metastatic Renal Cell Carcinoma (SWITCH-II)
NCT01762592	PHASE3	WITHDRAWN	REDECT 2: REnal Masses: Pivotal Trial to DEteCT Clear Cell Renal Cell Carcinoma With PET/CT
NCT01865747	PHASE3	COMPLETED	A Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma