UQCRFS1

Summary

UQCRFS1 (ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1, HGNC:12587) is a protein-coding gene on chromosome 19q12, encoding Cytochrome b-c1 complex subunit Rieske, mitochondrial (P47985). 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: 77.5% of cell lines).

Predicted to enable oxidoreductase activity. Involved in mitochondrial respiratory chain complex III assembly and respiratory electron transport chain. Located in mitochondrion. Part of respiratory chain complex III. Implicated in mitochondrial complex III deficiency.

Source: NCBI Gene 7386 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex III deficiency, nuclear type 10 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 32 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 24
• Cancer dependency (DepMap): dependent in 77.5% of screened cell lines
• MANE Select transcript: NM_006003

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12587
Approved symbol	UQCRFS1
Name	ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1
Location	19q12
Locus type	gene with protein product
Status	Approved
Aliases	ISP, RIS1, RIP1, UQCR5, RISP
Ensembl gene	ENSG00000169021
Ensembl biotype	protein_coding
OMIM	191327
Entrez	7386

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000304863, ENST00000933914

RefSeq mRNA: 1 — MANE Select: NM_006003 NM_006003

CCDS: CCDS12415

Canonical transcript exons

ENST00000304863 — 2 exons

Exon	Start	End
ENSE00001124391	29205320	29208158
ENSE00001124397	29212905	29213151

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 97.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 140.1226 / max 826.4427, expressed in 1827 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180351	140.1226	1827

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	97.95	gold quality
heart left ventricle	UBERON:0002084	97.58	gold quality
mucosa of transverse colon	UBERON:0004991	97.54	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.49	gold quality
muscle of leg	UBERON:0001383	97.44	gold quality
apex of heart	UBERON:0002098	97.25	gold quality
right atrium auricular region	UBERON:0006631	97.14	gold quality
skeletal muscle tissue	UBERON:0001134	96.47	gold quality
heart	UBERON:0000948	96.39	gold quality
adrenal tissue	UBERON:0018303	96.27	gold quality
right adrenal gland	UBERON:0001233	95.81	gold quality
right adrenal gland cortex	UBERON:0035827	95.74	gold quality
rectum	UBERON:0001052	95.61	gold quality
adult mammalian kidney	UBERON:0000082	95.30	gold quality
transverse colon	UBERON:0001157	95.03	gold quality
left adrenal gland	UBERON:0001234	94.94	gold quality
muscle tissue	UBERON:0002385	94.91	gold quality
left adrenal gland cortex	UBERON:0035825	94.49	gold quality
adrenal gland	UBERON:0002369	94.45	gold quality
duodenum	UBERON:0002114	94.12	gold quality
prefrontal cortex	UBERON:0000451	93.57	gold quality
colon	UBERON:0001155	93.55	gold quality
kidney	UBERON:0002113	93.41	gold quality
anterior cingulate cortex	UBERON:0009835	93.18	gold quality
body of stomach	UBERON:0001161	93.10	gold quality
frontal cortex	UBERON:0001870	93.07	gold quality
intestine	UBERON:0000160	92.93	gold quality
islet of Langerhans	UBERON:0000006	92.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.80	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-8559	no	740.94
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ZNF331

miRNA regulators (miRDB)

29 targeting UQCRFS1, 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-607	99.97	73.62	5593
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-205-3P	99.92	69.92	3165
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-4711-3P	98.97	66.87	1020
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-4272	98.76	68.74	1810
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-3184-3P	96.96	66.91	845
HSA-MIR-6857-3P	96.70	65.43	915

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 77.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• UQCRFS1 gene appears to be involved in development of more aggressive phenotype of breast cancer. (PMID:15047214)
• UQCRFS1/RISP knockdown in breast tumor cell line led to decreased mitochondrial membrane potential as well as a decrease in matrigel invasion. (PMID:21901141)
• UQCRFS1 produces N-terminal polypeptides, which remain bound to holocomplex III. We show that, in normal conditions, these UQCRFS1 fragments are rapidly removed, but when TTC19 is absent they accumulate within complex III, causing its structural and functional impairment. (PMID:28673544)
• Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis. (PMID:31883641)
• Pulse-chase SILAC-based analyses reveal selective oversynthesis and rapid turnover of mitochondrial protein components of respiratory complexes. (PMID:31974161)
• Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-kappaB/cyclin D1 pathway. (PMID:32669538)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	uqcrfs1	ENSDARG00000007745
mus_musculus	Uqcrfs1	ENSMUSG00000038462
rattus_norvegicus	Uqcrfs1	ENSRNOG00000018281
drosophila_melanogaster	RFeSP	FBGN0021906
caenorhabditis_elegans		WBGENE00002162

Protein

Protein identifiers

Cytochrome b-c1 complex subunit Rieske, mitochondrial — P47985 (reviewed: P47985)

Alternative names: Complex III subunit 5, Cytochrome b-c1 complex subunit 5, Rieske iron-sulfur protein, Rieske protein UQCRFS1, Ubiquinol-cytochrome c reductase iron-sulfur subunit

All UniProt accessions (1): P47985

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 Rieske protein is a catalytic core subunit containing a [2Fe-2S] iron-sulfur cluster. It cycles between 2 conformational states during catalysis to transfer electrons from the quinol bound in the Q(0) site in cytochrome b to cytochrome c1. Incorporation of UQCRFS1 is the penultimate step in complex III assembly. Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII). UQCRFS1 undergoes proteolytic processing once it is incorporated in the complex III dimer. One of the fragments, called subunit 9, corresponds to its mitochondrial targeting sequence (MTS). The proteolytic processing is necessary for the correct insertion of UQCRFS1 in the complex III dimer, but the persistence of UQCRFS1-derived fragments may prevent newly imported UQCRFS1 to be processed and assembled into complex III and is detrimental for the complex III structure and function.

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)). Incorporation of the Rieske protein UQCRFS1 is the penultimate step in complex III assembly. Interacts with TTC19, which is involved in the clearance of UQCRFS1 fragments. Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII). Subunit 9 corresponds to the mitochondrial targeting sequence (MTS) of Rieske protein UQCRFS1. It is retained after processing and incorporated inside complex III, where it remains bound to the complex and localizes between the 2 core subunits UQCRC1/QCR1 and UQCRC2/QCR2.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. Proteolytic processing is necessary for the correct insertion of UQCRFS1 in the complex III dimer. Several fragments are generated during UQCRFS1 insertion, most probably due to the endogenous matrix-processing peptidase (MPP) activity of the 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, which are homologous to the 2 mitochondrial-processing peptidase (MPP) subunits beta-MPP and alpha-MPP respectively. The action of the protease is also necessary for the clearance of the UQCRFS1 fragments.

Disease relevance. Mitochondrial complex III deficiency, nuclear type 10 (MC3DN10) [MIM:618775] A form of mitochondrial complex III deficiency, a disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. MC3DN10 is an autosomal recessive form characterized by fetal bradycardia, poor feeding, hypotonia, hypertrophic cardiomyopathy, alopecia totalis, low mitochondrial complex III activity and lactic acidosis. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [2Fe-2S] cluster per subunit. Fe-S cluster delivery to the Rieske protein is mediated by components of the iron sulfur (Fe-S) cluster assembly machinery that reside in the mitochondrial matrix (including HSC20 and LYRM7).

Miscellaneous. The Rieske protein is a high potential 2Fe-2S protein.

Similarity. Belongs to the Rieske iron-sulfur protein family.

RefSeq proteins (1): NP_005994* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004192	Rieske_TM	Domain
IPR005805	Rieske_Fe-S_prot_C	Domain
IPR006317	Ubiquinol_cyt_c_Rdtase_Fe-S-su	Domain
IPR011070	Globular_prot_asu/bsu	Homologous_superfamily
IPR014349	Rieske_Fe-S_prot	Family
IPR015248	UQCRFS1_N	Domain
IPR017941	Rieske_2Fe-2S	Domain
IPR036922	Rieske_2Fe-2S_sf	Homologous_superfamily
IPR037008	bc1_Rieske_TM_sf	Homologous_superfamily

Pfam: PF00355, PF02921, PF09165

Catalyzed reactions (Rhea), 1 shown:

• a quinol + 2 Fe(III)-cytochrome c = a quinone + 2 Fe(II)-cytochrome c + 2 H(+)(out) (RHEA:11484)

UniProt features (40 total): strand 13, helix 6, binding site 5, turn 5, sequence variant 3, chain 2, topological domain 2, disulfide bond 1, sequence conflict 1, transmembrane region 1, domain 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-P47985-F1	81.60	0.66

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 (5): 241; 217; 219; 236; 239

Disulfide bonds (1): 222–238

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-BTA-9865881	Complex III assembly
R-CEL-9865881	Complex III assembly
R-DME-9865881	Complex III assembly
R-DRE-9865881	Complex III assembly
R-GGA-9865881	Complex III assembly
R-HSA-611105	Respiratory electron transport
R-HSA-9865881	Complex III assembly
R-MMU-9865881	Complex III assembly
R-RNO-9865881	Complex III assembly
R-SSC-9865881	Complex III assembly

MSigDB gene sets: 280 (showing top): MODULE_93, MODULE_151, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_UBE2I, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, MORF_HDAC1, MORF_UBE2N, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, MODULE_149, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_MITOCHONDRIAL_ELECTRON_TRANSPORT_UBIQUINOL_TO_CYTOCHROME_C, MORF_SKP1A, GOBP_OXIDATIVE_PHOSPHORYLATION

GO Biological Process (4): mitochondrial electron transport, ubiquinol to cytochrome c (GO:0006122), respiratory electron transport chain (GO:0022904), mitochondrial respiratory chain complex III assembly (GO:0034551), proton transmembrane transport (GO:1902600)

GO Molecular Function (6): quinol-cytochrome-c reductase activity (GO:0008121), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), 2 iron, 2 sulfur cluster binding (GO:0051537), protein binding (GO:0005515), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), respiratory chain complex III (GO:0045275), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Respiratory electron transport	1
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	3
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
electron transport chain	1
cellular respiration	1
respiratory chain complex III assembly	1
mitochondrial respiratory chain complex assembly	1
monoatomic cation transmembrane transport	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on diphenols and related substances as donors	1
active monoatomic ion transmembrane transporter activity	1
catalytic activity	1
cation binding	1
iron-sulfur cluster binding	1
binding	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1
cellular anatomical structure	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

3615 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UQCRFS1	MT-CYB	P00156	999
UQCRFS1	CYC1	P08574	999
UQCRFS1	UQCRC2	P22695	988
UQCRFS1	CYCS	P00001	949
UQCRFS1	UQCRC1	P31930	922
UQCRFS1	ATP5MC3	P48201	920
UQCRFS1	ATP5MC1	P05496	918
UQCRFS1	ATP5MC2	Q06055	918
UQCRFS1	UQCRB	P14927	913
UQCRFS1	LYRM7	Q5U5X0	864
UQCRFS1	UQCR11	O14957	848
UQCRFS1	NDUFB9	Q9Y6M9	836
UQCRFS1	UQCRQ	O14949	833
UQCRFS1	UQCR10	Q9UDW1	827
UQCRFS1	SDHA	P31040	819

IntAct

108 interactions, top by confidence:

A	B	Type	Score
UQCRFS1	LYRM7	psi-mi:“MI:0915”(physical association)	0.790
LYRM7	UQCRFS1	psi-mi:“MI:0915”(physical association)	0.790
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
LYRM7	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
UQCRQ	COX7A2L	psi-mi:“MI:0914”(association)	0.640
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
ERBB2	HAX1	psi-mi:“MI:0914”(association)	0.530
LYRM7	HSPA9	psi-mi:“MI:0914”(association)	0.460
UQCRFS1	HSPA9	psi-mi:“MI:0914”(association)	0.460
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
	UQCRFS1	psi-mi:“MI:0915”(physical association)	0.400
UQCRFS1	HTR6	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (278): UQCRFS1 (Affinity Capture-RNA), UQCRFS1 (Affinity Capture-RNA), UQCRFS1 (Affinity Capture-Western), UQCRFS1 (Affinity Capture-Western), UQCRFS1 (Affinity Capture-Western), ALDH1B1 (Co-fractionation), COX6B1 (Co-fractionation), CYC1 (Co-fractionation), CYCS (Co-fractionation), GAA (Co-fractionation), LGALS1 (Co-fractionation), MDH1 (Co-fractionation), CYTB (Co-fractionation), NDUFA9 (Co-fractionation), PGM1 (Co-fractionation)

ESM2 similar proteins: A0A0D1DWQ2, A0A348AXY2, A0A348HAY9, A7T395, B8MKY9, B8MKZ5, C5PIJ9, C8VJZ7, D3ZKV9, I1R9B4, O13740, O13881, O42666, P0C7P4, P0CM51, P0CV11, P12556, P13157, P33802, P47985, Q03508, Q04564, Q09288, Q0V147, Q17QJ0, Q42652, Q4W9G3, Q587E3, Q5AQZ4, Q5AR53, Q5BAP2, Q5TEA3, Q69BJ6, Q69BK0, Q69BK1, Q69BK2, Q69BK3, Q69BK4, Q69BK5, Q69BK6

Diamond homologs: A0A1D8PJX3, A2BPU5, A2BVC4, A2C0R9, A2C7F6, A3PBI5, A5GMW1, A5GRU8, A8G3H7, A9BE84, B0JXB7, B2J3K2, B8HNR1, D5ANZ2, O07622, O31214, O49078, P05417, P07056, P08067, P08980, P0C7P4, P0C8N7, P0C8N8, P0CY48, P13272, P14698, P20788, P23136, P26290, P26291, P26292, P30361, P37841, P47985, P49727, P49728, P49729, P51130, P51132

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UQCRFS1	“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 97 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	7	43.9×	2e-08
Complex I biogenesis	12	28.4×	2e-12
Respiratory electron transport	18	24.5×	4e-18
Aerobic respiration and respiratory electron transport	11	13.9×	3e-08
Mitochondrial protein degradation	6	9.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	9	38.4×	4e-10
cellular respiration	7	36.0×	2e-07
aerobic respiration	12	35.4×	5e-13
proton motive force-driven mitochondrial ATP synthesis	10	31.4×	3e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	21
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
619297	NM_006003.3(UQCRFS1):c.215-1G>C	Pathogenic
619499	NM_006003.3(UQCRFS1):c.610C>T (p.Arg204Ter)	Pathogenic
619501	NM_006003.3(UQCRFS1):c.41T>A (p.Val14Asp)	Pathogenic
442775	GRCh37/hg19 19q11-12(chr19:28271107-31110233)x1	Likely pathogenic

SpliceAI

205 predictions. Top by Δscore:

Variant	Effect	Δscore
19:29208155:GGGA:G	acceptor_gain	1.0000
19:29208156:GGA:G	acceptor_gain	1.0000
19:29208159:C:CC	acceptor_gain	1.0000
19:29212900:CTCA:C	donor_loss	1.0000
19:29212901:TCACC:T	donor_loss	1.0000
19:29212902:CAC:C	donor_loss	1.0000
19:29212904:C:CG	donor_loss	1.0000
19:29208154:AGGGA:A	acceptor_gain	0.9900
19:29208156:GGAC:G	acceptor_loss	0.9900
19:29208157:GA:G	acceptor_gain	0.9900
19:29208158:AC:A	acceptor_loss	0.9900
19:29212899:GCTCA:G	donor_loss	0.9900
19:29212903:A:AC	donor_gain	0.9900
19:29212904:C:CC	donor_gain	0.9900
19:29209720:C:CT	acceptor_gain	0.9700
19:29209721:T:TT	acceptor_gain	0.9700
19:29212903:AC:A	donor_gain	0.9500
19:29212904:CC:C	donor_gain	0.9500
19:29212904:CCA:C	donor_gain	0.9500
19:29212962:C:CA	donor_gain	0.9400
19:29208167:C:CT	acceptor_gain	0.9300
19:29208171:C:CT	acceptor_gain	0.9000
19:29208129:C:CC	acceptor_gain	0.8900
19:29212924:G:GT	donor_gain	0.8900
19:29213106:C:CT	donor_gain	0.8900
19:29213107:T:TT	donor_gain	0.8900
19:29209719:A:AC	acceptor_gain	0.8800
19:29208131:G:C	acceptor_gain	0.8600
19:29208126:TGT:T	acceptor_gain	0.8400
19:29208163:A:T	acceptor_gain	0.8100

AlphaMissense

1755 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:29207868:A:G	W169R	0.998
19:29207868:A:T	W169R	0.998
19:29207745:A:G	W210R	0.997
19:29207745:A:T	W210R	0.997
19:29207602:G:C	N257K	0.996
19:29207602:G:T	N257K	0.996
19:29207629:C:A	R248S	0.996
19:29207629:C:G	R248S	0.996
19:29207630:C:A	R248M	0.996
19:29207630:C:G	R248T	0.996
19:29207723:C:T	C217Y	0.996
19:29207866:C:A	W169C	0.996
19:29207866:C:G	W169C	0.996
19:29207722:G:C	C217W	0.995
19:29207836:T:A	R179S	0.995
19:29207836:T:G	R179S	0.995
19:29207848:A:C	F175L	0.995
19:29207848:A:T	F175L	0.995
19:29207850:A:G	F175L	0.995
19:29207724:A:G	C217R	0.994
19:29207837:C:G	R179T	0.994
19:29207666:C:T	C236Y	0.993
19:29207667:A:G	C236R	0.993
19:29207702:G:T	P224H	0.993
19:29207843:C:G	R177P	0.993
19:29207846:A:T	V176E	0.993
19:29207708:C:G	C222S	0.992
19:29207709:A:T	C222S	0.992
19:29207849:A:C	F175C	0.992
19:29207633:C:T	G247D	0.991

dbSNP variants (sampled 300 via entrez): RS1000205251 (19:29212557 C>G), RS1000669897 (19:29205559 A>G), RS1000696135 (19:29210091 A>G), RS1001225396 (19:29212741 G>A), RS1001548473 (19:29205903 T>C), RS1001615950 (19:29209797 A>G), RS1001732861 (19:29214972 A>G), RS1002057064 (19:29212871 C>G,T), RS1002409439 (19:29211281 G>C), RS1002669205 (19:29206065 C>A,G,T), RS1003178548 (19:29208568 T>G), RS1003327062 (19:29214101 C>T), RS1003617634 (19:29212091 TTCTC>T), RS1004181762 (19:29204839 T>C), RS1004636631 (19:29212504 T>C)

Disease associations

OMIM: gene MIM:191327 | disease phenotypes: MIM:606054, MIM:618775

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex III deficiency, nuclear type 10	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 (5): cardiomyopathy (MONDO:0004994), lactic acidosis (MONDO:0006040), propionic acidemia (MONDO:0011628), mitochondrial complex III deficiency, nuclear type 10 (MONDO:0032909), mitochondrial complex III deficiency (MONDO:0015448)

Orphanet (2): Rare cardiomyopathy (Orphanet:167848), Propionic acidemia (Orphanet:35)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001081	Cholelithiasis
HP:0001085	Papilledema
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001324	Muscle weakness
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001629	Ventricular septal defect
HP:0001639	Hypertrophic cardiomyopathy
HP:0001662	Bradycardia
HP:0001698	Pericardial effusion
HP:0001873	Thrombocytopenia
HP:0001895	Normochromic anemia
HP:0001928	Abnormality of coagulation
HP:0002045	Hypothermia
HP:0002883	Hyperventilation
HP:0003128	Lactic acidosis
HP:0003236	Elevated circulating creatine kinase concentration
HP:0004897	Stress/infection-induced lactic acidosis
HP:0005301	Persistent left superior vena cava
HP:0007418	Alopecia totalis
HP:0008872	Feeding difficulties in infancy
HP:0011726	Persistent fetal circulation

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004136_10	Methadone dose in opioid dependence	6.000000e-06
GCST005359_25	Disease progression in age-related macular degeneration	6.000000e-06
GCST011176_26	Stroke	6.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007907	methadone dose measurement
EFO:0008336	disease progression measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000140	Acidosis, Lactic	C18.452.076.176.180
D009202	Cardiomyopathies	C14.280.238
D056693	Propionic Acidemia	C16.320.565.100.823; C18.452.648.100.823

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Cadmium	increases abundance, increases expression	2
Hydrogen Peroxide	affects reaction, decreases expression, decreases reaction	2
Cadmium Chloride	increases expression, increases abundance	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
deoxynivalenol	decreases expression	1
hesperetin	affects binding	1
perfluorooctanoic acid	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
corosolic acid	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
MT19c compound	decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Antimycin A	decreases expression	1
Doxorubicin	increases expression	1
Fluorouracil	affects expression	1
Isoniazid	decreases expression	1
Ivermectin	decreases expression	1
Lead	affects methylation	1
Lipopolysaccharides	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00185250	PHASE2	COMPLETED	Betaferon/ Betaseron (Interferon Beta-1b) in Patients With Chronic Viral Cardiomyopathy
NCT00490347	PHASE2	COMPLETED	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Feasibility Trial
NCT00694161	PHASE2	COMPLETED	The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy