SDHAF4

Summary

SDHAF4 (succinate dehydrogenase complex assembly factor 4, HGNC:20957) is a protein-coding gene on chromosome 6q13, encoding Succinate dehydrogenase assembly factor 4, mitochondrial (Q5VUM1). 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….

Predicted to enable enzyme activator activity. Involved in cellular respiration and mitochondrial respiratory chain complex II assembly. Located in mitochondrion.

Source: NCBI Gene 135154 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_145267

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20957
Approved symbol	SDHAF4
Name	succinate dehydrogenase complex assembly factor 4
Location	6q13
Locus type	gene with protein product
Status	Approved
Aliases	Sdh8
Ensembl gene	ENSG00000154079
Ensembl biotype	protein_coding
OMIM	619198
Entrez	135154

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000370474, ENST00000468640

RefSeq mRNA: 1 — MANE Select: NM_145267 NM_145267

CCDS: CCDS4972

Canonical transcript exons

ENST00000370474 — 3 exons

Exon	Start	End
ENSE00001013963	70579414	70579566
ENSE00001452812	70588615	70589569
ENSE00003533264	70566930	70567004

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 86.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.7324 / max 341.5905, expressed in 1802 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68473	19.7324	1802

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	86.42	gold quality
islet of Langerhans	UBERON:0000006	85.89	gold quality
prefrontal cortex	UBERON:0000451	84.92	gold quality
adrenal tissue	UBERON:0018303	84.69	gold quality
cortical plate	UBERON:0005343	83.55	gold quality
muscle of leg	UBERON:0001383	82.83	gold quality
calcaneal tendon	UBERON:0003701	82.24	gold quality
gastrocnemius	UBERON:0001388	82.18	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.10	gold quality
heart left ventricle	UBERON:0002084	82.01	gold quality
hypothalamus	UBERON:0001898	81.94	gold quality
anterior cingulate cortex	UBERON:0009835	81.90	gold quality
right adrenal gland	UBERON:0001233	81.66	gold quality
cardiac ventricle	UBERON:0002082	81.65	gold quality
apex of heart	UBERON:0002098	81.62	gold quality
right adrenal gland cortex	UBERON:0035827	81.25	gold quality
left adrenal gland	UBERON:0001234	81.19	gold quality
right atrium auricular region	UBERON:0006631	81.15	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.10	gold quality
left adrenal gland cortex	UBERON:0035825	81.10	gold quality
ganglionic eminence	UBERON:0004023	80.97	gold quality
frontal cortex	UBERON:0001870	80.85	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.85	gold quality
neocortex	UBERON:0001950	80.83	gold quality
adrenal gland	UBERON:0002369	80.63	gold quality
heart	UBERON:0000948	80.49	gold quality
caput epididymis	UBERON:0004358	80.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.39	gold quality
monocyte	CL:0000576	80.33	gold quality
nucleus accumbens	UBERON:0001882	80.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting SDHAF4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255
HSA-MIR-4670-3P	97.37	68.35	1378

Literature-anchored findings (GeneRIF, showing 1)

• THADA, SDHAF4, and MACF1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes. (PMID:36672824)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sdhaf4	ENSDARG00000039390
mus_musculus	Sdhaf4	ENSMUSG00000026154
rattus_norvegicus	Sdhaf4	ENSRNOG00000072946
drosophila_melanogaster	CG15283	FBGN0028844
drosophila_melanogaster	Sirup	FBGN0031971
caenorhabditis_elegans	W02D3.12	WBGENE00020937

Protein

Protein identifiers

Succinate dehydrogenase assembly factor 4, mitochondrial — Q5VUM1 (reviewed: Q5VUM1)

All UniProt accessions (1): Q5VUM1

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. Binds to the flavoprotein subunit SDHA in its FAD-bound form, blocking the generation of excess reactive oxygen species (ROS) and facilitating its assembly with the iron-sulfur protein subunit SDHB into the SDH catalytic dimer.

Subunit / interactions. Interacts with SDHA in its FAD-bound form.

Subcellular location. Mitochondrion matrix.

Similarity. Belongs to the SDHAF4 family.

RefSeq proteins (1): NP_660310* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012875	SDHF4	Family

Pfam: PF07896

UniProt features (12 total): strand 2, compositionally biased region 2, sequence variant 2, turn 2, transit peptide 1, chain 1, region of interest 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8DYE	X-RAY DIFFRACTION	1.44
8DYD	X-RAY DIFFRACTION	1.52

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VUM1-F1	65.37	0.00

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: 70 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_PROTEIN_MATURATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MARTINEZ_RB1_TARGETS_DN, GOBP_PROTEIN_FOLDING, GOBP_CELLULAR_RESPIRATION, GOCC_MITOCHONDRIAL_MATRIX, GOMF_ENZYME_ACTIVATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, CHICAS_RB1_TARGETS_SENESCENT, GOBP_TRICARBOXYLIC_ACID_CYCLE, GOMF_PROTEIN_FOLDING_CHAPERONE, FOXN3_TARGET_GENES

GO Biological Process (5): tricarboxylic acid cycle (GO:0006099), mitochondrial respiratory chain complex II assembly (GO:0034553), innate immune response (GO:0045087), cellular respiration (GO:0045333), protein folding (GO:0006457)

GO Molecular Function (3): enzyme activator activity (GO:0008047), protein folding chaperone (GO:0044183), protein binding (GO:0005515)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

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
mitochondrion	2
aerobic respiration	1
primary metabolic process	1
mitochondrial respiratory chain complex assembly	1
respiratory chain complex II assembly	1
immune response	1
defense response to symbiont	1
energy derivation by oxidation of organic compounds	1
cellular process	1
protein maturation	1
catalytic activity	1
enzyme regulator activity	1
molecular function activator activity	1
molecular_function	1
protein folding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

576 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SDHAF4	SDHAF2	Q9NX18	895
SDHAF4	SDHAF3	Q9NRP4	883
SDHAF4	SDHAF1	A6NFY7	835
SDHAF4	F5H5T6	F5H5T6	828
SDHAF4	SDHC	Q99643	675
SDHAF4	SDHD	O14521	642
SDHAF4	SDHA	P31040	637
SDHAF4	LYRM7	Q5U5X0	541
SDHAF4	SDHB	P21912	540
SDHAF4	COA4	Q9NYJ1	507
SDHAF4	COX17	Q14061	492
SDHAF4	COX18	Q8N8Q8	453
SDHAF4	LACC1	Q8IV20	443
SDHAF4	UQCC2	Q9BRT2	436
SDHAF4	MIPEP	Q99797	405

IntAct

19 interactions, top by confidence:

A	B	Type	Score
SDHA	SDHB	psi-mi:“MI:0914”(association)	0.820
SDHAF3	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
CYB5B	SDHAF4	psi-mi:“MI:0915”(physical association)	0.560
CD81	SDHAF4	psi-mi:“MI:0915”(physical association)	0.560
UPK1B	SDHAF4	psi-mi:“MI:0915”(physical association)	0.560
SDHAF4	PPTC7	psi-mi:“MI:0914”(association)	0.350
SDHAF4	GPX4	psi-mi:“MI:0914”(association)	0.350
SDHA	FLOT1	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
CD81	SDHAF4	psi-mi:“MI:0915”(physical association)	0.000
UPK1B	SDHAF4	psi-mi:“MI:0915”(physical association)	0.000
CYB5B	SDHAF4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): C6orf57 (Affinity Capture-MS), GLRX5 (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), TMLHE (Affinity Capture-MS), ECH1 (Affinity Capture-MS), C6orf57 (Affinity Capture-MS), C6orf57 (Affinity Capture-MS), C6orf57 (Two-hybrid), C6orf57 (Two-hybrid), C6orf57 (Two-hybrid), C6orf57 (Negative Genetic), C6orf57 (Affinity Capture-MS), C6orf57 (Affinity Capture-MS), NLN (Co-fractionation)

ESM2 similar proteins: A0A0N7L4N2, A2YX04, A5DKB1, A5HWA8, C5DDY0, C5E2Q0, F1MCY2, F1QIC4, G2TRM8, G2TRP3, O18195, O36399, O45952, O60291, O94328, P0CO33, P19955, P48306, P52871, P62512, P9WES8, Q04907, Q09446, Q09705, Q09750, Q23523, Q2V2Q3, Q32L85, Q3ZBW7, Q5VUM1, Q5XII9, Q61733, Q621Z7, Q6DJR9, Q6Z8M8, Q753Y5, Q89420, Q8BTE0, Q8C9X6, Q8K190

Diamond homologs: C6Y4C4, P38345, Q54Y25, Q5VUM1, Q8BTE0, Q4UKG8, Q92J60, Q9VLU6, Q9ZDZ6, A8EXV6, A8F0E8, A8F1Y8, A8F2B0, A8GNE3, A8GQJ7, A8GS98, A8GSI6, A8GT27, B0BUL7, B0BVY4, B0BXR2, B0BY00, C3PM75, C3PNK4, C3PNS9, C4K0F2, C4K162, C4K265, Q1RGX4, Q1RIS8, Q4UKI8, Q4ULJ9, Q4ULU3, Q4UMI9, Q4UMX8, Q4UNC8, Q4UND5, Q92H06, Q92H07, Q92HR5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

726 predictions. Top by Δscore:

Variant	Effect	Δscore
6:70567005:G:GG	donor_gain	1.0000
6:70579404:A:AG	acceptor_gain	1.0000
6:70579410:CTA:C	acceptor_loss	1.0000
6:70579411:TAGGA:T	acceptor_loss	1.0000
6:70579412:A:AG	acceptor_gain	1.0000
6:70579412:A:AT	acceptor_loss	1.0000
6:70579412:AG:A	acceptor_gain	1.0000
6:70579413:G:GC	acceptor_gain	1.0000
6:70579413:GG:G	acceptor_gain	1.0000
6:70579413:GGA:G	acceptor_gain	1.0000
6:70579413:GGAT:G	acceptor_gain	1.0000
6:70579413:GGATC:G	acceptor_gain	1.0000
6:70579562:GGAAA:G	donor_gain	1.0000
6:70579563:GAAA:G	donor_gain	1.0000
6:70579563:GAAAG:G	donor_gain	1.0000
6:70579564:A:T	donor_gain	1.0000
6:70579564:AAA:A	donor_gain	1.0000
6:70579564:AAAGT:A	donor_loss	1.0000
6:70579565:AA:A	donor_gain	1.0000
6:70579567:GT:G	donor_loss	1.0000
6:70579567:GTAA:G	donor_gain	1.0000
6:70579568:T:G	donor_loss	1.0000
6:70588613:A:AG	acceptor_gain	1.0000
6:70588614:G:GA	acceptor_gain	1.0000
6:70567001:GCAA:G	donor_gain	0.9900
6:70567002:CAAGT:C	donor_loss	0.9900
6:70567004:AG:A	donor_loss	0.9900
6:70567513:GCAAA:G	donor_gain	0.9900
6:70567517:A:AG	donor_gain	0.9900
6:70567517:A:G	donor_gain	0.9900

AlphaMissense

684 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:70588719:T:C	F108L	0.998
6:70588721:T:A	F108L	0.998
6:70588721:T:G	F108L	0.998
6:70588694:G:C	W99C	0.997
6:70588694:G:T	W99C	0.997
6:70588692:T:A	W99R	0.996
6:70588692:T:C	W99R	0.996
6:70588699:G:C	R101P	0.994
6:70588720:T:C	F108S	0.994
6:70588712:T:G	C105W	0.992
6:70588720:T:G	F108C	0.992
6:70588707:C:A	R104S	0.991
6:70588708:G:C	R104P	0.991
6:70588704:G:A	G103R	0.989
6:70588704:G:C	G103R	0.989
6:70588681:G:C	R95P	0.987
6:70588705:G:A	G103E	0.987
6:70588711:G:A	C105Y	0.986
6:70588649:A:C	E84D	0.985
6:70588649:A:T	E84D	0.985
6:70588690:A:T	D98V	0.985
6:70588691:T:A	D98E	0.985
6:70588691:T:G	D98E	0.985
6:70588697:A:C	E100D	0.985
6:70588697:A:T	E100D	0.985
6:70588705:G:T	G103V	0.985
6:70588718:T:A	D107E	0.985
6:70588718:T:G	D107E	0.985
6:70588693:G:T	W99L	0.984
6:70588710:T:C	C105R	0.984

dbSNP variants (sampled 300 via entrez): RS1000112844 (6:70585667 G>A), RS1000187244 (6:70585208 A>T), RS1000364817 (6:70596895 C>G,T), RS1000422459 (6:70573512 C>T), RS1000455519 (6:70573180 T>C), RS1000512558 (6:70597179 G>A), RS1000649552 (6:70589385 C>G,T), RS1000703227 (6:70579167 A>G), RS1000715538 (6:70595404 G>A), RS1000899650 (6:70566295 A>G), RS1000962667 (6:70571982 T>A,G), RS1001082082 (6:70572425 T>C), RS1001147136 (6:70591215 A>G), RS1001299623 (6:70570589 C>T), RS1001374841 (6:70566707 A>C)

Disease associations

OMIM: gene MIM:619198 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001033_11	Type 2 diabetes	3.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	7
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	increases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Dimethyl Sulfoxide	affects expression	1
Niclosamide	increases expression	1
Oxygen	increases expression	1
Quercetin	increases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Urethane	decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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