UQCRC2

Summary

UQCRC2 (ubiquinol-cytochrome c reductase core protein 2, HGNC:12586) is a protein-coding gene on chromosome 16p12.2, encoding Cytochrome b-c1 complex subunit 2, mitochondrial (P22695). Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation. It is a selective cancer dependency (DepMap: 61.7% of cell lines).

The protein encoded by this gene is located in the mitochondrion, where it is part of the ubiquinol-cytochrome c reductase complex (also known as complex III). This complex constitutes a part of the mitochondrial respiratory chain. Defects in this gene are a cause of mitochondrial complex III deficiency nuclear type 5.

Source: NCBI Gene 7385 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex III deficiency nuclear type 5 (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 54 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 61.7% of screened cell lines
• MANE Select transcript: NM_003366

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12586
Approved symbol	UQCRC2
Name	ubiquinol-cytochrome c reductase core protein 2
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Aliases	QCR2, UQCR2
Ensembl gene	ENSG00000140740
Ensembl biotype	protein_coding
OMIM	191329
Entrez	7385

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 25 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay

ENST00000268379, ENST00000561553, ENST00000561798, ENST00000563711, ENST00000563898, ENST00000564095, ENST00000565331, ENST00000565464, ENST00000567597, ENST00000567757, ENST00000567810, ENST00000618892, ENST00000630839, ENST00000864412, ENST00000864413, ENST00000864414, ENST00000864415, ENST00000864416, ENST00000864417, ENST00000864418, ENST00000938840, ENST00000938841, ENST00000938842, ENST00000938843, ENST00000938844, ENST00000951967, ENST00000951968, ENST00000951969, ENST00000951970, ENST00000951971, ENST00000951972, ENST00000951973, ENST00000951974

RefSeq mRNA: 1 — MANE Select: NM_003366 NM_003366

CCDS: CCDS10601

Canonical transcript exons

ENST00000268379 — 14 exons

Exon	Start	End
ENSE00000944763	21957235	21957318
ENSE00000944764	21957417	21957566
ENSE00000944765	21958535	21958599
ENSE00000944773	21976167	21976243
ENSE00001261363	21983088	21983660
ENSE00003491722	21971525	21971620
ENSE00003522522	21962761	21962885
ENSE00003540577	21968628	21968685
ENSE00003597890	21962460	21962516
ENSE00003603905	21973896	21973976
ENSE00003617623	21971923	21972122
ENSE00003664885	21980547	21980700
ENSE00003784480	21965408	21965505
ENSE00003894159	21953361	21953456

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 141.6724 / max 1350.0957, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153119	132.2463	1824
153118	9.4260	1720

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.60	gold quality
body of tongue	UBERON:0011876	99.40	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.34	gold quality
jejunal mucosa	UBERON:0000399	99.30	gold quality
apex of heart	UBERON:0002098	99.29	gold quality
jejunum	UBERON:0002115	99.28	gold quality
duodenum	UBERON:0002114	99.24	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.23	gold quality
rectum	UBERON:0001052	99.22	gold quality
biceps brachii	UBERON:0001507	99.21	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.21	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.20	gold quality
mucosa of transverse colon	UBERON:0004991	99.20	gold quality
right atrium auricular region	UBERON:0006631	99.20	gold quality
germinal epithelium of ovary	UBERON:0001304	99.15	gold quality
epithelium of nasopharynx	UBERON:0001951	99.13	gold quality
nasopharynx	UBERON:0001728	99.12	gold quality
cardiac ventricle	UBERON:0002082	99.11	gold quality
heart left ventricle	UBERON:0002084	99.10	gold quality
colonic mucosa	UBERON:0000317	99.09	gold quality
diaphragm	UBERON:0001103	99.08	gold quality
tongue	UBERON:0001723	99.07	gold quality
renal medulla	UBERON:0000362	99.05	gold quality
transverse colon	UBERON:0001157	99.04	gold quality
triceps brachii	UBERON:0001509	99.04	gold quality
adrenal tissue	UBERON:0018303	99.02	gold quality
cortical plate	UBERON:0005343	99.00	gold quality
gingival epithelium	UBERON:0001949	98.96	gold quality
large intestine	UBERON:0000059	98.92	gold quality
colon	UBERON:0001155	98.91	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	717.84
E-MTAB-6075	no	491.45
E-CURD-112	no	2.89
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting UQCRC2, 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-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-532-5P	98.43	67.53	760
HSA-MIR-633	98.35	69.45	1167
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-6881-5P	98.16	67.38	665
HSA-MIR-4421	97.99	64.89	701
HSA-MIR-5699-3P	97.81	65.00	861
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-424-3P	97.20	65.86	385
HSA-MIR-3126-3P	97.17	66.51	468

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 61.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• These data indicate that a homozygous missense mutation in UQCRC2 causes moderately impaired CIII function and severely decreased amounts of CIII and supercomplex, which would be the primary molecular pathogenesis in the patients. (PMID:23281071)
• Down-regulation of UQCRC2 partly reversed the inhibition of invasion/migration ability and chemoresistance in CDH18 overexpressed glioma cell lines. (PMID:30078018)
• These results provided novel insights into the potential role of UQCRC2 in the tumorigenesis and progression of colorectal cancer (PMID:30115536)
• our study as presented here identify the mitochondrial protein QCR2 as a novel suppressor of p53 to negatively regulate its stability and activity, and this suppression can be potentially reversed by another mitochondrial protein PHB. (PMID:30674441)
• AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy. (PMID:33719895)
• Homozygous missense mutation in UQCRC2 associated with severe encephalomyopathy, mitochondrial complex III assembly defect and activation of mitochondrial protein quality control. (PMID:33865955)
• Circular RNA hsa_circ_0000751 serves as a microRNA-488 sponge to suppress gastric cancer progression via ubiquinol-cytochrome c reductase core protein 2 regulation. (PMID:34565283)
• UQCRC2-related mitochondrial complex III deficiency, about 7 patients. (PMID:36509339)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	uqcrc2b	ENSDARG00000071691
mus_musculus	Uqcrc2	ENSMUSG00000030884
rattus_norvegicus	Uqcrc2	ENSRNOG00000036742
caenorhabditis_elegans		WBGENE00011679

Paralogs (6): UQCRC1 (ENSG00000010256), NRDC (ENSG00000078618), PMPCB (ENSG00000105819), PITRM1 (ENSG00000107959), IDE (ENSG00000119912), PMPCA (ENSG00000165688)

Protein

Protein identifiers

Cytochrome b-c1 complex subunit 2, mitochondrial — P22695 (reviewed: P22695)

Alternative names: Complex III subunit 2, Core protein II, Ubiquinol-cytochrome-c reductase complex core protein 2

All UniProt accessions (7): P22695, A0A087WVZ4, H3BP04, H3BRG4, H3BSJ9, H3BUE4, H3BUI9

UniProt curated annotations — full annotation on UniProt →

Function. Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane, with protons being carried across the membrane as hydrogens on the quinol. In the process called Q cycle, 2 protons are consumed from the matrix, 4 protons are released into the intermembrane space and 2 electrons are passed to cytochrome c. The 2 core subunits UQCRC1/QCR1 and UQCRC2/QCR2 are homologous to the 2 mitochondrial-processing peptidase (MPP) subunits beta-MPP and alpha-MPP respectively, and they seem to have preserved their MPP processing properties. May be involved in the in situ processing of UQCRFS1 into the mature Rieske protein and its mitochondrial targeting sequence (MTS)/subunit 9 when incorporated into complex III.

Subunit / interactions. Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits. The complex is composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske protein UQCRFS1. The complex exists as an obligatory dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and cytochrome c oxidase (complex IV, CIV), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)). Interacts with RAB5IF. Interacts with STMP1.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex III deficiency, nuclear type 5 (MC3DN5) [MIM:615160] A disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase M16 family. UQCRC2/QCR2 subfamily.

RefSeq proteins (1): NP_003357* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001431	Pept_M16_Zn_BS	Binding_site
IPR007863	Peptidase_M16_C	Domain
IPR011249	Metalloenz_LuxS/M16	Homologous_superfamily
IPR011765	Pept_M16_N	Domain
IPR050361	MPP/UQCRC_Complex	Family

Pfam: PF00675, PF05193

UniProt features (48 total): helix 21, strand 13, sequence variant 5, modified residue 3, turn 3, transit peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9HZL	ELECTRON MICROSCOPY	2.52
9CG3	ELECTRON MICROSCOPY	2.96
5XTE	ELECTRON MICROSCOPY	3.4
5XTH	ELECTRON MICROSCOPY	3.9
5XTI	ELECTRON MICROSCOPY	17.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22695-F1	90.18	0.84

Functional residue map

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

Post-translational modifications (3): 66, 199, 250

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9865881	Complex III assembly

MSigDB gene sets: 261 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, MODULE_93, GOMF_METALLOPEPTIDASE_ACTIVITY, MODULE_151, MODULE_77, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_HDAC1, MORF_RAD21, TGACCTY_ERR1_Q2, MORF_HDAC2, MODULE_149, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_MITOCHONDRIAL_ELECTRON_TRANSPORT_UBIQUINOL_TO_CYTOCHROME_C, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_ELECTRON_TRANSPORT_CHAIN

GO Biological Process (5): oxidative phosphorylation (GO:0006119), mitochondrial electron transport, ubiquinol to cytochrome c (GO:0006122), proteolysis (GO:0006508), aerobic respiration (GO:0009060), cellular respiration (GO:0045333)

GO Molecular Function (3): metalloendopeptidase activity (GO:0004222), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex III (GO:0045275), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Metabolism of proteins	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
aerobic respiration	1
proton motive force-driven ATP synthesis	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
protein metabolic process	1
cellular respiration	1
energy derivation by oxidation of organic compounds	1
endopeptidase activity	1
metallopeptidase activity	1
cation binding	1
binding	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1

Protein interactions and networks

STRING

3746 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UQCRC2	UQCRFS1	P47985	988
UQCRC2	UQCRB	P14927	979
UQCRC2	MT-CO1	P00395	978
UQCRC2	SDHB	P21912	977
UQCRC2	UQCRC1	P31930	973
UQCRC2	NDUFB8	O95169	947
UQCRC2	SDHA	P31040	914
UQCRC2	NLRX1	Q86UT6	909
UQCRC2	CYC1	P08574	904
UQCRC2	UQCRQ	O14949	899
UQCRC2	NDUFA9	Q16795	890
UQCRC2	COX4I1	P13073	867
UQCRC2	ATP5F1A	P25705	867
UQCRC2	MT-CYB	P00156	852
UQCRC2	UQCR10	Q9UDW1	839

IntAct

297 interactions, top by confidence:

A	B	Type	Score
UQCRC1	UQCRQ	psi-mi:“MI:0915”(physical association)	0.740
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
UQCRQ	COX7A2L	psi-mi:“MI:0914”(association)	0.640
UQCRB	COX7A2L	psi-mi:“MI:0914”(association)	0.640
UQCRH	COX7A2L	psi-mi:“MI:0914”(association)	0.640
UQCRC2	ACAP1	psi-mi:“MI:0915”(physical association)	0.560
UQCRC2	SNW1	psi-mi:“MI:0915”(physical association)	0.560
UQCRC2	LHX5	psi-mi:“MI:0915”(physical association)	0.560
	UQCRC2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (464): UQCRC2 (Affinity Capture-MS), UQCRC2 (Affinity Capture-MS), UQCRC2 (Affinity Capture-MS), UQCRC2 (Affinity Capture-MS), UQCRC2 (Affinity Capture-MS), UQCRC2 (Affinity Capture-MS), AFG3L2 (Co-fractionation), ATAD3A (Co-fractionation), ATP5A1 (Co-fractionation), ATP5C1 (Co-fractionation), CCT8 (Co-fractionation), CLTC (Co-fractionation), COPB1 (Co-fractionation), COX4I1 (Co-fractionation), DDX39B (Co-fractionation)

ESM2 similar proteins: A0A1D8PP59, C0HK54, C0HK56, J9VPD8, O02640, O04308, O42908, O60044, O74190, O94745, P07256, P07257, P09457, P0CN60, P0CN61, P10507, P11914, P22695, P23004, P29677, P32551, P32898, P39692, P43265, P78700, P78761, P83782, P97997, P98080, Q09878, Q4IA56, Q4WP38, Q54F93, Q5B6H7, Q5Y223, Q6BPY6, Q6C0U8, Q6C2E3, Q6C877, Q6C9B1

Diamond homologs: O04308, O94745, P10507, P11913, P11914, P20069, P22695, P23004, P23955, P29677, P32551, P97997, Q0P5M8, Q10713, Q42290, Q5R513, Q9DB77, Q9DC61, Q9P7X1, Q9ZU25, Q00302, O75439, P31930, Q03346, Q3SZ71, Q5REK3, Q68FY0, Q9CXT8, Q9CZ13

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UQCRC2	“form complex”	“CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 198 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Complex III assembly	5	17.0×	2e-03
Complex IV assembly	7	12.4×	5e-04
Respiratory electron transport	15	11.1×	3e-09

GO biological processes:

GO term	Partners	Fold	FDR
cellular respiration	9	22.9×	2e-07
mitochondrial electron transport, cytochrome c to oxygen	5	22.5×	1e-03
regulation of postsynaptic membrane neurotransmitter receptor levels	5	14.6×	6e-03
protein localization to plasma membrane	9	5.8×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	26
Likely benign	17
Benign	4

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
4848961	NC_000016.9:g.(?21964681)(21994982_?)del	Pathogenic
996066	NM_003366.4(UQCRC2):c.665G>C (p.Gly222Ala)	Pathogenic
3780779	NM_003366.4(UQCRC2):c.1048-2A>C	Likely pathogenic

SpliceAI

2659 predictions. Top by Δscore:

Variant	Effect	Δscore
16:21957410:A:G	acceptor_gain	1.0000
16:21957415:A:AG	acceptor_gain	1.0000
16:21957416:G:GG	acceptor_gain	1.0000
16:21957565:TGGTG:T	donor_loss	1.0000
16:21957567:G:A	donor_loss	1.0000
16:21957568:T:A	donor_loss	1.0000
16:21957569:GA:G	donor_loss	1.0000
16:21958532:A:AG	acceptor_gain	1.0000
16:21958532:AAGAC:A	acceptor_gain	1.0000
16:21958533:A:G	acceptor_gain	1.0000
16:21962757:GTA:G	acceptor_loss	1.0000
16:21962758:TAGT:T	acceptor_loss	1.0000
16:21962759:A:AG	acceptor_gain	1.0000
16:21962759:AGT:A	acceptor_gain	1.0000
16:21962760:G:GA	acceptor_gain	1.0000
16:21962760:GT:G	acceptor_gain	1.0000
16:21962760:GTG:G	acceptor_gain	1.0000
16:21962760:GTGAT:G	acceptor_gain	1.0000
16:21962881:GACTC:G	donor_gain	1.0000
16:21962882:ACTC:A	donor_gain	1.0000
16:21962883:CTC:C	donor_gain	1.0000
16:21962884:TC:T	donor_gain	1.0000
16:21962885:CG:C	donor_loss	1.0000
16:21962886:G:GG	donor_gain	1.0000
16:21962886:GT:G	donor_loss	1.0000
16:21962887:T:A	donor_loss	1.0000
16:21962890:G:GG	donor_gain	1.0000
16:21965402:TCACA:T	acceptor_loss	1.0000
16:21965404:ACAG:A	acceptor_loss	1.0000
16:21965405:CA:C	acceptor_loss	1.0000

AlphaMissense

2942 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:21965435:C:A	A181D	0.991
16:21973939:G:A	G337E	0.991
16:21958569:G:C	R101P	0.990
16:21957448:C:A	A50D	0.987
16:21962816:T:A	W149R	0.986
16:21962816:T:C	W149R	0.986
16:21968680:G:A	G222E	0.986
16:21972019:T:A	V288D	0.986
16:21973938:G:T	G337W	0.986
16:21983134:G:A	G442E	0.986
16:21957504:A:C	S69R	0.985
16:21957506:T:A	S69R	0.985
16:21957506:T:G	S69R	0.985
16:21971961:G:C	A269P	0.985
16:21972022:T:C	L289P	0.985
16:21983091:G:C	A428P	0.985
16:21973903:C:A	A325E	0.984
16:21958590:G:A	G108D	0.983
16:21962475:G:C	R116S	0.983
16:21962475:G:T	R116S	0.983
16:21962477:A:T	E117V	0.983
16:21980555:T:C	L378P	0.983
16:21983127:G:C	A440P	0.983
16:21962818:G:C	W149C	0.982
16:21962818:G:T	W149C	0.982
16:21957450:T:C	S51P	0.981
16:21965467:T:C	C192R	0.981
16:21971932:G:C	R259P	0.981
16:21973930:G:A	G334E	0.981
16:21973938:G:A	G337R	0.981

dbSNP variants (sampled 300 via entrez): RS1000016179 (16:21967433 G>A,T), RS1000023294 (16:21961172 A>C), RS1000060314 (16:21954018 C>T), RS1000084276 (16:21977578 A>G), RS1000135137 (16:21968865 A>G), RS1000220662 (16:21982215 C>T), RS1000263754 (16:21970235 G>A), RS1000340792 (16:21956705 T>G), RS1000373484 (16:21956486 A>G), RS1000478860 (16:21963622 C>G,T), RS1000559440 (16:21977283 G>A), RS1000633811 (16:21974005 C>A,G,T), RS1000795013 (16:21980947 G>C), RS1000871748 (16:21952670 A>G), RS1000925967 (16:21983127 G>A)

Disease associations

OMIM: gene MIM:191329 | disease phenotypes: MIM:615160

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex III deficiency nuclear type 5	Strong	Autosomal recessive
mitochondrial complex III deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (3): mitochondrial complex III deficiency nuclear type 5 (MONDO:0014066), mitochondrial disease (MONDO:0044970), mitochondrial complex III deficiency (MONDO:0015448)

Orphanet (1): Mitochondrial disease (Orphanet:68380)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0001263	Global developmental delay
HP:0001410	Decreased liver function
HP:0001518	Small for gestational age
HP:0001631	Atrial septal defect
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001987	Hyperammonemia
HP:0002033	Poor suck
HP:0002151	Increased circulating lactate concentration
HP:0002572	Episodic vomiting
HP:0002876	Episodic tachypnea
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003348	Hyperalaninemia
HP:0003542	Increased circulating pyruvate concentration
HP:0033177	Elevated circulating suberic acid concentration
HP:0033325	Elevated circulating sebacic acid concentration
HP:0033504	Elevated circulating fumarate concentration

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066941 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.23	Kd	5.842	nM	CHEMBL3752910
8.23	ED50	5.842	nM	CHEMBL3752910
8.21	Kd	6.162	nM	CHEMBL5653589
8.21	ED50	6.162	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149736: Binding affinity to human UQCRC2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0058	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149736: Binding affinity to human UQCRC2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0062	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases reaction, affects expression, decreases expression, increases expression	4
sodium arsenite	increases expression, decreases expression, increases abundance	4
Acetaminophen	decreases expression	3
Hydrogen Peroxide	decreases reaction, increases expression, affects cotreatment, affects reaction, decreases expression	3
bisphenol F	affects cotreatment, decreases expression, increases expression	2
Resveratrol	affects cotreatment, increases expression	2
Vorinostat	increases expression, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression	2
Arsenic	decreases expression, increases abundance, increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Dronabinol	decreases expression	2
1-Methyl-4-phenylpyridinium	decreases expression, increases reaction	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
quinomethionate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
lead acetate	decreases expression, decreases reaction, increases abundance	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
cobaltous chloride	decreases expression	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
epigallocatechin gallate	affects cotreatment, affects reaction, decreases expression, decreases reaction	1
gallocatechol	decreases expression, decreases reaction, affects cotreatment, affects reaction	1
epicatechin gallate	affects cotreatment, affects reaction, decreases expression, decreases reaction	1
chromium hexavalent ion	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652778	Binding	Binding affinity to human UQCRC2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies