SDHAF2

Summary

SDHAF2 (succinate dehydrogenase complex assembly factor 2, HGNC:26034) is a protein-coding gene on chromosome 11q12.2, encoding Succinate dehydrogenase assembly factor 2, mitochondrial (Q9NX18). 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 transport chain, and which couples the oxidation…. It is a selective cancer dependency (DepMap: 38.7% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a mitochondrial assembly factor needed for the flavination of a succinate dehydrogenase complex subunit (SDHA), which is required for activity of the succinate dehydrogenase complex. Mutations in this gene are associated with paraganglioma.

Source: NCBI Gene 54949 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary pheochromocytoma-paraganglioma (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 747 total — 18 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 51
• Cancer dependency (DepMap): dependent in 38.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_017841

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26034
Approved symbol	SDHAF2
Name	succinate dehydrogenase complex assembly factor 2
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20487, SDH5
Ensembl gene	ENSG00000167985
Ensembl biotype	protein_coding
OMIM	613019
Entrez	54949

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 7 nonsense_mediated_decay, 1 retained_intron

ENST00000301761, ENST00000359614, ENST00000534878, ENST00000536250, ENST00000537782, ENST00000542074, ENST00000542794, ENST00000543265, ENST00000713959, ENST00000713960, ENST00000713961, ENST00000713962, ENST00000713963, ENST00000713964, ENST00000713965, ENST00000713966, ENST00000857230, ENST00000964796

RefSeq mRNA: 1 — MANE Select: NM_017841 NM_017841

CCDS: CCDS8007

Canonical transcript exons

ENST00000301761 — 4 exons

Exon	Start	End
ENSE00004021994	61438004	61438113
ENSE00004021996	61445941	61446733
ENSE00004021999	61437625	61437848
ENSE00004022003	61430124	61430182

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 94.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.5978 / max 177.2784, expressed in 1821 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114581	28.3957	1816
114580	8.2021	1784

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	94.85	gold quality
adenohypophysis	UBERON:0002196	94.53	gold quality
granulocyte	CL:0000094	94.46	gold quality
leukocyte	CL:0000738	93.79	gold quality
monocyte	CL:0000576	93.64	gold quality
ileal mucosa	UBERON:0000331	93.43	gold quality
apex of heart	UBERON:0002098	93.24	gold quality
mucosa of transverse colon	UBERON:0004991	93.23	gold quality
right adrenal gland	UBERON:0001233	93.19	gold quality
left adrenal gland	UBERON:0001234	93.08	gold quality
right adrenal gland cortex	UBERON:0035827	93.01	gold quality
gastrocnemius	UBERON:0001388	92.92	gold quality
left adrenal gland cortex	UBERON:0035825	92.92	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.86	gold quality
muscle of leg	UBERON:0001383	92.49	gold quality
right atrium auricular region	UBERON:0006631	92.46	gold quality
right lobe of liver	UBERON:0001114	92.45	gold quality
pituitary gland	UBERON:0000007	92.29	gold quality
lower esophagus mucosa	UBERON:0035834	92.26	gold quality
rectum	UBERON:0001052	92.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.86	gold quality
adrenal gland	UBERON:0002369	91.85	gold quality
smooth muscle tissue	UBERON:0001135	91.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.53	gold quality
right lobe of thyroid gland	UBERON:0001119	91.46	gold quality
heart left ventricle	UBERON:0002084	91.44	gold quality
gall bladder	UBERON:0002110	91.44	gold quality
body of stomach	UBERON:0001161	91.41	gold quality
left lobe of thyroid gland	UBERON:0001120	91.39	gold quality
bone marrow cell	CL:0002092	91.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting SDHAF2, 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-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-6884-3P	98.05	65.32	750
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-6781-3P	97.44	66.85	970
HSA-MIR-937-5P	97.43	68.39	667

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 38.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• germline loss-of-function mutations in the SDH5 gene segregate with disease in a family with hereditary paraganglioma (PMID:19628817)
• Somatic mutations of the SDHAF2 tumor suppressor gene are unlikely to frequently contribute to parathyroid tumor development in sporadic primary hyperparathyroidism. (PMID:20972721)
• We established the SDHAF2 mutation status of PGL2 family members (PMID:21224366)
• Studies indicate that an array of tumor syndromes caused by complex II-associated mutations in genes SDHA, SDHB, SDHC, SDHD, SDHAF1 and SDHAF2 have been identified over a decade. (PMID:23174333)
• Studies indicate that mutations in the mitochondrial complex II structural subunit genes SDHB, SDHC and SDHD and the regulatory subunit gene SDHAF2 in many paraganglioma families. (PMID:23291190)
• Studies indicate that the flavinylation factor Sdh5 (SDHAF2) provided insight into the possible mechanism associated with Sdh1 (SDHA) flavinylation. (PMID:23380393)
• Data indicate that succinate dehydrogenase 5 (SDH5) functions as a critical protein in regulating epithelial-mesenchymal transition (EMT) by modulating the glycogen synthase kinase (GSK)-3beta-beta-catenin signaling pathway. (PMID:23983127)
• Loss of heterozygosity was found in more than 50 % of the von Hippel-Lindau-associated pheochromocytomas, and was correlated with a significant decrease (p < 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. (PMID:24322175)
• Data indicate that SDH5 is protected from mitochondrial LON (LONM)-mediated degradation in mitochondria by its stable interaction with SDHA, a state that is dysregulated in hereditary paraganglioma 2 (PGL2). (PMID:24414418)
• New mutation found in SDHAF2 gene in pheochromocytoma/paraganglioma patients. (PMID:24712571)
• Autosomal dominant susceptibility for Paraganglioma is modified by imprinting and mutations in the SDHAF2 gene cause Paragangliomas only when the mutation is inherited from father. (PMID:24973967)
• FAD interacts noncovalently with SDHA in the absence of SDH5 (PMID:27296776)
• data show that SDHA flavination is independent of SDHAF2 in breast cancer cells, employing an alternative mechanism. (PMID:27587393)
• Loss of SDHAF2 gene is associated with paragangliomas. (PMID:28099933)
• The SDHA, TMEM127, MAX, and SDHAF2 genes contribute to hereditary pheochromocytoma and paraganglioma. (PMID:28384794)
• SDH5 Depletion Enhances Radiosensitivity by Regulating p53: A New Method for Noninvasive Prediction of Radiotherapy Response. (PMID:31588224)
• The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein. (PMID:32887801)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sdhaf2	ENSDARG00000062971
mus_musculus	Sdhaf2	ENSMUSG00000024668
rattus_norvegicus	Sdhaf2	ENSRNOG00000020646
drosophila_melanogaster	CG14757	FBGN0033274
drosophila_melanogaster	CG12895	FBGN0033523
caenorhabditis_elegans		WBGENE00013269

Protein

Protein identifiers

Succinate dehydrogenase assembly factor 2, mitochondrial — Q9NX18 (reviewed: Q9NX18)

All UniProt accessions (13): A0AAQ5BH68, A0AAQ5BH75, A0AAQ5BH77, A0AAQ5BH83, A0AAQ5BH90, A0AAQ5BH98, A0AAQ5BHA2, F5H4T4, F5H8E2, F8W679, Q9NX18, M0QY91, M0QYN2

UniProt curated annotations — full annotation on UniProt →

Function. 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 transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. Required for flavinylation (covalent attachment of FAD) of the flavoprotein subunit SDHA of the SDH catalytic dimer.

Subunit / interactions. Interacts with SDHA within the SDH catalytic dimer.

Subcellular location. Mitochondrion matrix.

Disease relevance. Pheochromocytoma/paraganglioma syndrome 2 (PPGL2) [MIM:601650] 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. PPGL2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SDHAF2 family.

RefSeq proteins (1): NP_060311* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005631	SDH	Family
IPR028882	SDHAF2	Family
IPR036714	SDH_sf	Homologous_superfamily

Pfam: PF03937

UniProt features (12 total): helix 9, transit peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8DYD	X-RAY DIFFRACTION	1.52
6VAX	X-RAY DIFFRACTION	2.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX18-F1	84.06	0.64

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-71403	Citric acid cycle (TCA cycle)

MSigDB gene sets: 248 (showing top): GCANCTGNY_MYOD_Q6, MAZ_Q6, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, STAT3_01, SP1_Q2_01, CREB_Q4, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_OXIDATIVE_PHOSPHORYLATION, GATA1_01, GOBP_ELECTRON_TRANSPORT_CHAIN

GO Biological Process (7): tricarboxylic acid cycle (GO:0006099), mitochondrial electron transport, succinate to ubiquinone (GO:0006121), protein dephosphorylation (GO:0006470), negative regulation of epithelial to mesenchymal transition (GO:0010719), protein-FAD linkage (GO:0018293), mitochondrial respiratory chain complex II assembly (GO:0034553), negative regulation of canonical Wnt signaling pathway (GO:0090090)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): nucleolus (GO:0005730), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification process	2
mitochondrion	2
cytoplasm	2
aerobic respiration	1
primary metabolic process	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
dephosphorylation	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
mitochondrial respiratory chain complex assembly	1
respiratory chain complex II assembly	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1362 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SDHAF2	SDHA	P31040	999
SDHAF2	SDHD	O14521	999
SDHAF2	SDHC	Q99643	999
SDHAF2	SDHB	P21912	998
SDHAF2	SDHAF1	A6NFY7	927
SDHAF2	SDHAF4	Q5VUM1	895
SDHAF2	TMEM127	O75204	886
SDHAF2	SDHAF3	Q9NRP4	845
SDHAF2	RET	P07949	697
SDHAF2	NF1	P21359	666
SDHAF2	MAX	P25912	625
SDHAF2	EGLN1	Q9GZT9	593
SDHAF2	EPAS1	Q99814	591
SDHAF2	FH	P07954	589
SDHAF2	KIF1B	O60333	582
SDHAF2	MEN1	O00255	582

IntAct

18 interactions, top by confidence:

A	B	Type	Score
SDHA	SDHB	psi-mi:“MI:0914”(association)	0.820
SDHAF2	SDHA	psi-mi:“MI:0915”(physical association)	0.740
SEC22A	SDHAF2	psi-mi:“MI:0915”(physical association)	0.560
CYP4F2	SDHAF2	psi-mi:“MI:0915”(physical association)	0.560
SDHAF2	HSPA8	psi-mi:“MI:0914”(association)	0.350
SDHA	FLOT1	psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350
INSR	ATOX1	psi-mi:“MI:0914”(association)	0.350
SEC22A	SDHAF2	psi-mi:“MI:0915”(physical association)	0.000
CYP4F2	SDHAF2	psi-mi:“MI:0915”(physical association)	0.000
SDHAF2	EEF1A1	psi-mi:“MI:0915”(physical association)	0.000
SDHAF2	ELP1	psi-mi:“MI:0915”(physical association)	0.000
SDHAF2	IMMT	psi-mi:“MI:0915”(physical association)	0.000
SDHAF2	CCDC90B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (37): ABCA2 (Affinity Capture-MS), CTNNA2 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), HSPA9 (Affinity Capture-MS), RRM2 (Affinity Capture-MS), SDHA (Affinity Capture-MS), SLC1A5 (Affinity Capture-MS), CORO2A (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), NOL8 (Affinity Capture-MS), SSX2IP (Affinity Capture-MS), CWF19L2 (Affinity Capture-MS), SDHAF2 (Affinity Capture-MS), SDHAF2 (Affinity Capture-RNA), IMMT (Two-hybrid)

ESM2 similar proteins: A1Z897, A3GHR8, A3KP74, A5DJ67, A5DT64, A6ZND9, A8XYZ2, B0VYX5, B0VYX6, B0XK69, B1P1W2, B3LIY9, B3MGU5, B3MI37, B3N6D9, B3N8S9, B4GDB3, B4GG58, B4HMQ1, B4HRL4, B4J5U3, B4KN44, B4KPG8, B4LKE5, B4MRE7, B4N665, B4NXN5, B4P2P8, B4QFP7, B4QID8, B5DZ31, B5E0U2, B6JZ70, B9W8P6, P0CR32, P0CR33, Q08230, Q10440, Q178L7, Q3ZBC2

Diamond homologs: A1Z897, A3GHR8, A3KP74, A5DJ67, A5DT64, A6ZND9, A8XYZ2, B0XK69, B1P1W2, B3LIY9, B3MGU5, B3MI37, B3N6D9, B3N8S9, B4GDB3, B4GG58, B4HMQ1, B4HRL4, B4J5U3, B4KN44, B4KPG8, B4LKE5, B4MRE7, B4N665, B4NXN5, B4P2P8, B4QFP7, B4QID8, B5DZ31, B5E0U2, B6HRA4, B6JZ70, B8NT06, B9W8P6, C4R0B5, P0CR32, P0CR33, Q08230, Q0CSY3, Q10440

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SDHAF2	up-regulates	SDHB	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	17
Uncertain significance	418
Likely benign	204
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067840	NC_000011.9:g.(?61205087)(61213543_?)del	Pathogenic
1069215	NM_017841.4(SDHAF2):c.124del (p.Asp42fs)	Pathogenic
1441880	NM_017841.4(SDHAF2):c.216T>A (p.Tyr72Ter)	Pathogenic
1782242	NM_017841.4(SDHAF2):c.189dup (p.Glu64fs)	Pathogenic
2018877	NM_017841.4(SDHAF2):c.89C>G (p.Ser30Ter)	Pathogenic
2070423	NM_017841.4(SDHAF2):c.283C>T (p.Gln95Ter)	Pathogenic
2625581	NM_017841.4(SDHAF2):c.233del (p.Gly78fs)	Pathogenic
3227050	NM_017841.4(SDHAF2):c.211_242del (p.Leu71fs)	Pathogenic
3227053	NM_017841.4(SDHAF2):c.313dup (p.Tyr105fs)	Pathogenic
3385978	NM_017841.4(SDHAF2):c.165dup (p.Gln56fs)	Pathogenic
3385979	NM_017841.4(SDHAF2):c.166C>T (p.Gln56Ter)	Pathogenic
3646144	NM_017841.4(SDHAF2):c.215_216del (p.Leu71_Tyr72insTer)	Pathogenic
401	NM_017841.4(SDHAF2):c.232G>A (p.Gly78Arg)	Pathogenic
4085561	NM_017841.4(SDHAF2):c.260+2T>A	Pathogenic
4844579	NM_017841.4(SDHAF2):c.295del (p.Glu99fs)	Pathogenic
4844582	NM_017841.4(SDHAF2):c.199dup (p.Arg67fs)	Pathogenic
532513	NM_017841.4(SDHAF2):c.177dup (p.Asp60Ter)	Pathogenic
820509	NM_017841.4(SDHAF2):c.201_205dup (p.Arg69fs)	Pathogenic
1067722	NM_017841.4(SDHAF2):c.260+2T>C	Likely pathogenic
2020736	NM_017841.4(SDHAF2):c.36+1G>A	Likely pathogenic
2678639	NM_017841.4(SDHAF2):c.301C>T (p.Gln101Ter)	Likely pathogenic
2698975	NM_017841.4(SDHAF2):c.261-1G>T	Likely pathogenic
2774506	NM_017841.4(SDHAF2):c.9_19del (p.Ser4fs)	Likely pathogenic
3240438	NM_017841.4(SDHAF2):c.406del (p.Val136fs)	Likely pathogenic
3251123	NM_017841.4(SDHAF2):c.348G>A (p.Trp116Ter)	Likely pathogenic
3572276	NM_017841.4(SDHAF2):c.29C>A (p.Ser10Ter)	Likely pathogenic
3632817	NM_017841.4(SDHAF2):c.261-2A>G	Likely pathogenic
3650061	NM_017841.4(SDHAF2):c.260+1G>C	Likely pathogenic
3951376	NM_017841.4(SDHAF2):c.370+1G>T	Likely pathogenic
3951377	NM_017841.4(SDHAF2):c.44dup (p.Leu16fs)	Likely pathogenic

SpliceAI

1001 predictions. Top by Δscore:

Variant	Effect	Δscore
11:61430189:A:T	donor_gain	1.0000
11:61438002:A:AG	acceptor_gain	1.0000
11:61438003:G:GA	acceptor_gain	1.0000
11:61438076:GCCTA:G	donor_gain	1.0000
11:61438081:G:GG	donor_gain	1.0000
11:61445940:GAA:G	acceptor_gain	1.0000
11:61436879:A:G	donor_gain	0.9900
11:61437822:A:T	donor_gain	0.9900
11:61437995:T:A	acceptor_gain	0.9900
11:61438003:GT:G	acceptor_gain	0.9900
11:61438003:GTC:G	acceptor_gain	0.9900
11:61438003:GTCT:G	acceptor_gain	0.9900
11:61438003:GTCTT:G	acceptor_gain	0.9900
11:61445939:A:AG	acceptor_gain	0.9900
11:61445940:G:GG	acceptor_gain	0.9900
11:61430107:G:GT	donor_gain	0.9800
11:61430183:G:GA	donor_loss	0.9800
11:61437995:T:TA	acceptor_loss	0.9800
11:61438000:TTAG:T	acceptor_loss	0.9800
11:61438001:TAGT:T	acceptor_loss	0.9800
11:61438002:A:G	acceptor_loss	0.9800
11:61438111:CAGGT:C	donor_loss	0.9800
11:61438112:AGGTA:A	donor_loss	0.9800
11:61438113:G:GT	donor_loss	0.9800
11:61438114:GT:G	donor_loss	0.9800
11:61438115:T:G	donor_loss	0.9800
11:61440714:TAGG:T	acceptor_gain	0.9800
11:61430133:TGC:T	donor_gain	0.9700
11:61430179:GCTG:G	donor_gain	0.9700
11:61430183:G:GG	donor_gain	0.9700

AlphaMissense

1095 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61437808:A:C	S74R	0.998
11:61437810:C:A	S74R	0.998
11:61437810:C:G	S74R	0.998
11:61437816:G:C	K76N	0.998
11:61437816:G:T	K76N	0.998
11:61437830:A:T	E81V	0.998
11:61437831:A:C	E81D	0.998
11:61437831:A:T	E81D	0.998
11:61438048:T:C	L102P	0.998
11:61438089:T:A	W116R	0.998
11:61438089:T:C	W116R	0.998
11:61437793:C:A	R69S	0.997
11:61437797:T:C	L70P	0.997
11:61437813:A:C	R75S	0.997
11:61437813:A:T	R75S	0.997
11:61437819:G:C	R77S	0.997
11:61437819:G:T	R77S	0.997
11:61437834:C:A	N82K	0.997
11:61437834:C:G	N82K	0.997
11:61438008:T:C	F89L	0.997
11:61438010:T:A	F89L	0.997
11:61438010:T:G	F89L	0.997
11:61438066:T:C	L108P	0.997
11:61438091:G:C	W116C	0.997
11:61438091:G:T	W116C	0.997
11:61438104:T:A	W121R	0.997
11:61438104:T:C	W121R	0.997
11:61437794:G:C	R69P	0.996
11:61437812:G:C	R75T	0.996
11:61437818:G:T	R77M	0.996

dbSNP variants (sampled 300 via entrez): RS1000099610 (11:61429038 A>T), RS1000114920 (11:61429657 C>A), RS1000168461 (11:61442213 T>C), RS1000242274 (11:61445071 A>T), RS1000275807 (11:61435674 C>A,T), RS1000387686 (11:61441958 A>G), RS1000439370 (11:61439411 G>A), RS1000456030 (11:61432965 T>A), RS1000459817 (11:61436006 C>T), RS1000498593 (11:61440645 GTAAATATAGA>G), RS1000591428 (11:61433176 C>G), RS1000737444 (11:61433342 G>A), RS1001107682 (11:61446280 G>A,T), RS1001200730 (11:61428723 G>A), RS1001290651 (11:61428858 T>A,C,G)

Disease associations

OMIM: gene MIM:613019 | disease phenotypes: MIM:168000, MIM:601650, MIM:167000

GenCC curated gene-disease

Disease	Classification	Inheritance
pheochromocytoma/paraganglioma syndrome 2	Definitive	Autosomal dominant
hereditary pheochromocytoma-paraganglioma	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary pheochromocytoma-paraganglioma	Definitive	AD

Mondo (4): hereditary pheochromocytoma-paraganglioma (MONDO:0017366), hereditary neoplastic syndrome (MONDO:0015356), pheochromocytoma/paraganglioma syndrome 2 (MONDO:0011121), ovarian cancer (MONDO:0008170)

Orphanet (3): Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Inherited cancer-predisposing syndrome (Orphanet:140162), Rare ovarian cancer (Orphanet:213500)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000405	Conductive hearing impairment
HP:0000526	Aniridia
HP:0000740	Episodic paroxysmal anxiety
HP:0000790	Hematuria
HP:0000980	Pallor
HP:0001069	Episodic hyperhidrosis
HP:0001095	Hypertensive retinopathy
HP:0001293	Cranial nerve compression
HP:0001337	Tremor
HP:0001342	Cerebral hemorrhage
HP:0001605	Vocal cord paralysis
HP:0001609	Hoarse voice
HP:0001618	Dysphonia
HP:0001635	Congestive heart failure
HP:0001686	Loss of voice
HP:0001824	Weight loss
HP:0001962	Palpitations
HP:0002018	Nausea
HP:0002331	Recurrent paroxysmal headache
HP:0002574	Episodic abdominal pain
HP:0002640	Hypertension associated with pheochromocytoma
HP:0002664	Neoplasm
HP:0002668	Paraganglioma
HP:0002864	Paraganglioma of head and neck
HP:0002886	Vagal paraganglioma
HP:0003001	Glomus jugular tumor
HP:0003072	Hypercalcemia

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
C566646	Paragangliomas 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Leflunomide	decreases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	increases expression	1
Gasoline	decreases expression, increases abundance, affects cotreatment	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases expression	1
Particulate Matter	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2EW	Abcam HeLa SDHAF2 KO	Cancer cell line	Female
CVCL_XS53	HAP1 SDHAF2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	PHASE4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	PHASE4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	PHASE4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	PHASE4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	PHASE4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	PHASE4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	PHASE4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	PHASE4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	PHASE4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	PHASE4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	PHASE4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	PHASE4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	PHASE4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	PHASE4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	PHASE4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	PHASE4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	PHASE4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	PHASE4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	PHASE4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	PHASE4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT00001806	PHASE3	COMPLETED	Methods in Education for Breast Cancer Genetics
NCT00002477	PHASE3	UNKNOWN	Adjuvant Chemotherapy Compared With Observation in Treating Patients With Resected Early Stage Ovarian Epithelial Cancer
NCT00002568	PHASE3	COMPLETED	Combination Chemotherapy With or Without Surgery in Treating Patients With Stage III Ovarian Epithelial Cancer
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002717	PHASE3	COMPLETED	Paclitaxel and Cisplatin in Treating Patients With Stage III or Stage IV Ovarian Cancer or Primary Peritoneal Cancer
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002819	PHASE3	TERMINATED	Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Persistent Ovarian Epithelial Cancer
NCT00002894	PHASE3	COMPLETED	Platinum-based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer
NCT00002895	PHASE3	COMPLETED	Early Chemotherapy Based on CA 125 Level Alone Compared With Delayed Chemotherapy in Treating Patients With Recurrent Ovarian Epithelial , Fallopian Tube, or Primary Peritoneal Cancer
NCT00003120	PHASE3	COMPLETED	S9701 Paclitaxel in Treating Patients With Advanced Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Remission
NCT00003214	PHASE3	COMPLETED	Chemosensitivity Testing to Assign Treatment for Patients With Stage III or Stage IV Ovarian Cancer
NCT00003322	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Primary Peritoneal or Stage III Epithelial Ovarian Cancer
NCT00003636	PHASE3	COMPLETED	Chemotherapy Plus Surgery in Treating Patients With Stage III or Stage IV Ovarian, Peritoneal, or Fallopian Tube Cancer
NCT00003644	PHASE3	COMPLETED	Carboplatin Plus Paclitaxel With or Without Continued Low-Dose Paclitaxel in Treating Patients With Early-Stage Ovarian Cancer