CYC1

Summary

CYC1 (cytochrome c1, HGNC:2579) is a protein-coding gene on chromosome 8q24.3, encoding Cytochrome c1, heme protein, mitochondrial (P08574). 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: 58.5% of cell lines).

This gene encodes a subunit of the cytochrome bc1 complex, which plays an important role in the mitochondrial respiratory chain by transferring electrons from the Rieske iron-sulfur protein to cytochrome c. Mutations in this gene may cause mitochondrial complex III deficiency, nuclear type 6.

Source: NCBI Gene 1537 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex III deficiency nuclear type 6 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 187 total — 4 pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 58.5% of screened cell lines
• MANE Select transcript: NM_001916

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2579
Approved symbol	CYC1
Name	cytochrome c1
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	UQCR4
Ensembl gene	ENSG00000179091
Ensembl biotype	protein_coding
OMIM	123980
Entrez	1537

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 21 protein_coding, 3 retained_intron

ENST00000318911, ENST00000525122, ENST00000528618, ENST00000533444, ENST00000876790, ENST00000876791, ENST00000876792, ENST00000876793, ENST00000876794, ENST00000876795, ENST00000876796, ENST00000876797, ENST00000915398, ENST00000915399, ENST00000915400, ENST00000915401, ENST00000915402, ENST00000965126, ENST00000965127, ENST00000965128, ENST00000965129, ENST00000965130, ENST00000965131, ENST00000965132

RefSeq mRNA: 1 — MANE Select: NM_001916 NM_001916

CCDS: CCDS6415

Canonical transcript exons

ENST00000318911 — 7 exons

Exon	Start	End
ENSE00001259023	144095833	144096029
ENSE00001259045	144095076	144095228
ENSE00003493232	144096337	144096494
ENSE00003531735	144097034	144097134
ENSE00003595222	144096124	144096250
ENSE00003646927	144097232	144097525
ENSE00003663592	144096584	144096744

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 74.0921 / max 383.6801, expressed in 1824 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91474	71.3251	1824
91473	2.4112	1242
91475	0.3558	152

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.43	gold quality
heart left ventricle	UBERON:0002084	99.21	gold quality
cardiac ventricle	UBERON:0002082	99.20	gold quality
left ventricle myocardium	UBERON:0006566	99.14	gold quality
mucosa of transverse colon	UBERON:0004991	99.11	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.09	gold quality
diaphragm	UBERON:0001103	99.06	gold quality
body of tongue	UBERON:0011876	99.06	gold quality
gastrocnemius	UBERON:0001388	99.01	gold quality
right atrium auricular region	UBERON:0006631	98.99	gold quality
heart right ventricle	UBERON:0002080	98.98	gold quality
cardiac atrium	UBERON:0002081	98.94	gold quality
vastus lateralis	UBERON:0001379	98.85	gold quality
quadriceps femoris	UBERON:0001377	98.80	gold quality
muscle organ	UBERON:0001630	98.68	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.68	gold quality
muscle of leg	UBERON:0001383	98.66	gold quality
triceps brachii	UBERON:0001509	98.63	gold quality
skeletal muscle tissue	UBERON:0001134	98.62	gold quality
heart	UBERON:0000948	98.61	gold quality
transverse colon	UBERON:0001157	98.61	gold quality
right adrenal gland	UBERON:0001233	98.60	gold quality
right adrenal gland cortex	UBERON:0035827	98.56	gold quality
left adrenal gland	UBERON:0001234	98.51	gold quality
myocardium	UBERON:0002349	98.44	gold quality
left adrenal gland cortex	UBERON:0035825	98.40	gold quality
muscle tissue	UBERON:0002385	98.34	gold quality
biceps brachii	UBERON:0001507	98.30	gold quality
body of stomach	UBERON:0001161	98.28	gold quality
endometrium epithelium	UBERON:0004811	98.24	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	20.41
E-CURD-112	yes	9.89
E-MTAB-7606	no	1586.20
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F6, ESRRA, NFYA, NFYB, POU1F1, SALL3, TBP

miRNA regulators (miRDB)

14 targeting CYC1, 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-4775	99.98	75.00	6394
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-3938	98.72	66.07	834
HSA-MIR-6781-3P	97.44	66.85	970
HSA-MIR-2682-3P	97.10	66.16	840
HSA-MIR-635	96.00	65.54	687
HSA-MIR-6774-5P	95.94	65.18	722

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 58.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• Addition of H202 to tendon fibroblasts in vitro resulted in oxidative stress-induced apoptosis and the release of CYC1. (PMID:12788227)
• the Ca(2+) spike, mitochondrial Bcl-2 presensitization, and subsequent Delta psi(m) transition, Bax translocation, and ROS generation are important upstream signals for cytochrome c release upon stimulation by a Bcl-2 inhibitor. (PMID:14966123)
• Sensitivity of Cyt c detection in -linked immunosorbent assay is reduced in the presence of serum leucine-rich alpha-2-glycoprotein-1. (PMID:16699948)
• Decreased electron Transport Complex IV activity is associated with ulcerative colitis. (PMID:20440543)
• HeLa cells expressing non-cleavable cytochrome c1 maintain mitochondrial morphology and functions. (PMID:21577235)
• Mutations in CYC1 cause insulin-responsive hyperglycemia. (PMID:23910460)
• our results provide evidence that CYC1 plays an important role in OS tumorigenesis, and modulation of CYC1 may be an effective strategy to potentiate OS to apoptotic induction by TRAIL. (PMID:25562155)
• FASL, granzyme B, and cytochrome c blood expression reflects breast cancer progression and response to therapy. (Review) (PMID:27117663)
• CYC1 promoted tumor metastasis via suppressing activation of AMPK and contributed to tumor growth via facilitating production of ATP. (PMID:27239088)
• results indicate that miR-661 plays a tumor suppressor role in OS mediated by the downregulation of CYC1, suggesting a potential mechanism underlying cell death resistance in Osteosarcoma. (PMID:28391262)
• these results indicate that CYC1 plays important roles in cell proliferation and comedo necrosis through the elevated oxidative phosphorylation activity in human ductal carcinoma in situ (PMID:28394473)
• CYC1 inhibits cell proliferation, glycolytic activity and increases chemosensitivity to paclitaxel in ER-positive breast carcinoma cells (PMID:31149728)
• Physical contact between cytochrome c1 and cytochrome c increases the driving force for electron transfer. (PMID:32717223)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyc1	ENSDARG00000038075
mus_musculus	Cyc1	ENSMUSG00000022551
rattus_norvegicus	Cyc1	ENSRNOG00000012457
drosophila_melanogaster	Cyt-c1	FBGN0035600
drosophila_melanogaster	Cyt-c1L	FBGN0039651
caenorhabditis_elegans	cyc-1	WBGENE00000869

Protein

Protein identifiers

Cytochrome c1, heme protein, mitochondrial — P08574 (reviewed: P08574)

Alternative names: Complex III subunit 4, Complex III subunit IV, Cytochrome b-c1 complex subunit 4, Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit

All UniProt accessions (1): P08574

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. Cytochrome c1 is a catalytic core subunit containing a c-type heme. It transfers electrons from the [2Fe-2S] iron-sulfur cluster of the Rieske protein to cytochrome c.

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 FLVCR2; this interaction occurs in the absence of heme and is disrupted upon heme binding.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex III deficiency, nuclear type 6 (MC3DN6) [MIM:615453] An autosomal recessive disorder caused by mitochondrial dysfunction. It is characterized by onset in early childhood of episodic acute lactic acidosis, ketoacidosis, and insulin-responsive hyperglycemia, usually associated with infection. Laboratory studies show decreased activity of mitochondrial complex III. Psychomotor development is normal. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 heme c group covalently per subunit.

Similarity. Belongs to the cytochrome c family.

RefSeq proteins (1): NP_001907* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002326	Cyt_c1	Family
IPR021157	Cyt_c1_TM_anchor_C	Homologous_superfamily
IPR036909	Cyt_c-like_dom_sf	Homologous_superfamily

Pfam: PF02167

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 (32 total): helix 9, strand 5, sequence variant 4, binding site 4, turn 3, topological domain 2, transit peptide 1, chain 1, modified residue 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-P08574-F1	86.37	0.75

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 (4): 121 (covalent); 124 (covalent); 125 (axial binding residue); 244 (axial binding residue)

Post-translational modifications (1): 182

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-611105	Respiratory electron transport
R-HSA-9865881	Complex III assembly

MSigDB gene sets: 292 (showing top): MORF_MTA1, MODULE_93, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BASSO_B_LYMPHOCYTE_NETWORK, ENK_UV_RESPONSE_KERATINOCYTE_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_UBE2I, MORF_HDAC1, MORF_RAD21, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, TGACCTY_ERR1_Q2, GOBP_MONOATOMIC_CATION_TRANSPORT, PATIL_LIVER_CANCER, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_RESPONSE_TO_GLUCAGON

GO Biological Process (4): mitochondrial electron transport, ubiquinol to cytochrome c (GO:0006122), response to glucagon (GO:0033762), cellular respiration (GO:0045333), proton transmembrane transport (GO:1902600)

GO Molecular Function (5): quinol-cytochrome-c reductase activity (GO:0008121), heme binding (GO:0020037), metal ion binding (GO:0046872), protein binding (GO:0005515), electron transfer activity (GO:0009055)

GO Cellular Component (5): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020), respiratory chain complex III (GO:0045275)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
response to peptide hormone	1
energy derivation by oxidation of organic compounds	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
tetrapyrrole binding	1
cation binding	1
binding	1
molecular_function	1
cytoplasm	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1

Protein interactions and networks

STRING

2807 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYC1	UQCRFS1	P47985	999
CYC1	MT-CYB	P00156	999
CYC1	CYCS	P00001	993
CYC1	UQCRB	P14927	978
CYC1	UQCRC1	P31930	944
CYC1	UQCRC2	P22695	904
CYC1	UQCRH	P07919	880
CYC1	UQCR10	Q9UDW1	840
CYC1	UQCRQ	O14949	773
CYC1	ATP5F1B	P06576	646
CYC1	SURF1	Q15526	640
CYC1	HCCS	P53701	627
CYC1	BCS1L	Q9Y276	618
CYC1	SDHA	P31040	617
CYC1	VDAC1	P21796	600

IntAct

100 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CYC1	HTT	psi-mi:“MI:0915”(physical association)	0.670
CYC1	UQCRB	psi-mi:“MI:0915”(physical association)	0.640
UQCRQ	COX7A2L	psi-mi:“MI:0914”(association)	0.640
UQCRB	COX7A2L	psi-mi:“MI:0914”(association)	0.640
	DDX3X	psi-mi:“MI:0914”(association)	0.630
CYC1	PDCD2	psi-mi:“MI:0915”(physical association)	0.560
ANKHD1	CYC1	psi-mi:“MI:0915”(physical association)	0.560
UQCRH	DCTN6	psi-mi:“MI:0914”(association)	0.530
PEX19	FAM20B	psi-mi:“MI:0914”(association)	0.530
PEX19	MYO1D	psi-mi:“MI:0914”(association)	0.530
Tubb4b	MGST3	psi-mi:“MI:0915”(physical association)	0.400
Haus1	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
PCNA	CYC1	psi-mi:“MI:0915”(physical association)	0.370
GOLT1B		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350

BioGRID (292): CYC1 (Affinity Capture-RNA), CYC1 (Affinity Capture-MS), CYC1 (Affinity Capture-MS), UQCR10 (Affinity Capture-MS), UQCRB (Affinity Capture-MS), AFG3L2 (Co-fractionation), ATAD3A (Co-fractionation), ATAD3B (Co-fractionation), ATP5I (Co-fractionation), ATP5O (Co-fractionation), CLTC (Co-fractionation), CYC1 (Co-fractionation), CYC1 (Co-fractionation), CYC1 (Co-fractionation), CYC1 (Co-fractionation)

ESM2 similar proteins: A0A1D8PHA3, D5ANZ4, O13966, O14321, O31216, O59680, O74198, O94609, P07142, P07143, P08574, P0CY49, P16243, P19414, P20114, P22178, P23135, P23368, P25087, P27443, P30594, P30595, P36444, P37222, P51615, P54385, P81379, P87111, Q00988, Q02760, Q08822, Q11190, Q12166, Q12632, Q4QAU9, Q54D07, Q54KB7, Q54XM6, Q55C16, Q6BRB7

Diamond homologs: A0A1D8PHA3, D5ANZ4, O59680, P00125, P07142, P07143, P08574, P0CY49, P13627, P20114, P23135, P25076, P29610, P51131, P81379, Q00988, Q02760, Q54D07, Q9D0M3, Q9FKS5, Q9LK29

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CYC1	“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 106 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	31.8×	6e-05
R-HSA-425366	6	15.8×	2e-04
Respiratory electron transport	8	11.0×	6e-05
SLC-mediated transmembrane transport	7	6.0×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
zinc ion transmembrane transport	5	40.4×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	101
Likely benign	56
Benign	16

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
4682716	GRCh37/hg19 8q24.3(chr8:144819498-145210080)x1	Pathogenic
625552	GRCh37/hg19 8q24.3(chr8:144879444-145199846)	Pathogenic
66019	NM_001916.5(CYC1):c.288G>T (p.Trp96Cys)	Pathogenic
66020	NM_001916.5(CYC1):c.643C>T (p.Leu215Phe)	Pathogenic

SpliceAI

1293 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144096122:A:AG	acceptor_gain	1.0000
8:144096123:G:GG	acceptor_gain	1.0000
8:144096123:GC:G	acceptor_gain	1.0000
8:144096224:G:GT	donor_gain	1.0000
8:144096227:G:GT	donor_gain	1.0000
8:144096231:C:CG	donor_gain	1.0000
8:144096231:C:G	donor_gain	1.0000
8:144096236:G:GT	donor_gain	1.0000
8:144096237:A:T	donor_gain	1.0000
8:144096248:G:GT	donor_gain	1.0000
8:144096333:GCAGG:G	acceptor_loss	1.0000
8:144096335:A:T	acceptor_loss	1.0000
8:144096336:G:A	acceptor_loss	1.0000
8:144096477:C:G	donor_gain	1.0000
8:144096490:GCTAG:G	donor_gain	1.0000
8:144096491:C:G	donor_gain	1.0000
8:144096492:TAGG:T	donor_loss	1.0000
8:144096493:AGGTA:A	donor_loss	1.0000
8:144096494:GGTA:G	donor_loss	1.0000
8:144096496:T:A	donor_loss	1.0000
8:144096579:CCTAG:C	acceptor_loss	1.0000
8:144096580:CTAG:C	acceptor_loss	1.0000
8:144096582:A:AG	acceptor_gain	1.0000
8:144096583:G:GG	acceptor_gain	1.0000
8:144096583:GGC:G	acceptor_gain	1.0000
8:144096583:GGCAT:G	acceptor_gain	1.0000
8:144097027:T:A	acceptor_gain	1.0000
8:144097030:CCAG:C	acceptor_loss	1.0000
8:144097031:CAGGC:C	acceptor_loss	1.0000
8:144097032:A:AG	acceptor_gain	1.0000

AlphaMissense

2081 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144096132:G:T	R112M	0.997
8:144096134:G:C	G113R	0.997
8:144096170:C:G	H125D	0.997
8:144096243:C:A	A149D	0.997
8:144096674:C:A	N234K	0.997
8:144096674:C:G	N234K	0.997
8:144097078:T:C	F273L	0.997
8:144097080:C:A	F273L	0.997
8:144097080:C:G	F273L	0.997
8:144097087:T:A	W276R	0.997
8:144097087:T:C	W276R	0.997
8:144096135:G:T	G113V	0.996
8:144096475:A:C	S198R	0.996
8:144096477:C:A	S198R	0.996
8:144096477:C:G	S198R	0.996
8:144096613:T:C	L214P	0.996
8:144096704:G:A	M244I	0.996
8:144096704:G:C	M244I	0.996
8:144096704:G:T	M244I	0.996
8:144097061:C:A	A267D	0.996
8:144097074:C:G	C271W	0.996
8:144097082:T:C	L274P	0.996
8:144097115:G:C	R285P	0.996
8:144095989:T:A	W96R	0.995
8:144095989:T:C	W96R	0.995
8:144096134:G:T	G113C	0.995
8:144096135:G:A	G113D	0.995
8:144096146:T:G	Y117D	0.995
8:144096159:G:A	C121Y	0.995
8:144096168:G:A	C124Y	0.995

dbSNP variants (sampled 300 via entrez): RS1000356964 (8:144094113 C>T), RS1000745188 (8:144097850 G>A), RS1002027014 (8:144095154 G>A,C), RS1003226376 (8:144096192 A>G), RS1003624852 (8:144096675 C>G,T), RS1004256932 (8:144093615 T>C,G), RS1004455164 (8:144093391 T>C), RS1004953171 (8:144097376 C>T), RS1006594181 (8:144097206 C>G,T), RS1006696830 (8:144096687 G>A,T), RS1007744252 (8:144095538 TC>T), RS1007802953 (8:144095829 G>A,C), RS1008843987 (8:144094745 G>A), RS1009865007 (8:144094174 G>A), RS1010414556 (8:144094455 G>A,C)

Disease associations

OMIM: gene MIM:123980 | disease phenotypes: MIM:615453, MIM:615583

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex III deficiency nuclear type 6	Definitive	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 6 (MONDO:0014194), 8q24.3 microdeletion syndrome (MONDO:0014263), mitochondrial complex III deficiency (MONDO:0015448)

Orphanet (1): 8q24.3 microdeletion syndrome (Orphanet:508488)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000508	Ptosis
HP:0001259	Coma
HP:0001298	Encephalopathy
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0001987	Hyperammonemia
HP:0001993	Ketoacidosis
HP:0002013	Vomiting
HP:0002151	Increased circulating lactate concentration
HP:0002344	Progressive neurologic deterioration
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002919	Ketonuria
HP:0003074	Hyperglycemia
HP:0003128	Lactic acidosis
HP:0003593	Infantile onset
HP:0005974	Episodic ketoacidosis
HP:0005979	Metabolic ketoacidosis
HP:0006554	Acute hepatic failure
HP:0011924	Decreased activity of mitochondrial complex III
HP:0032653	Elevated lactate:pyruvate ratio

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST009798_65	Asthma	1.000000e-08
GCST90002390_618	Mean corpuscular hemoglobin	3.000000e-20
GCST90002392_526	Mean corpuscular volume	8.000000e-21

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105975 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,395 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3301622	GILTERITINIB	4	2,395

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
9.26	Kd	0.55	nM	CHEMBL3752910
9.26	ED50	0.55	nM	CHEMBL3752910
7.53	Kd	29.28	nM	CHEMBL5653589
7.53	ED50	29.28	nM	CHEMBL5653589
6.70	Kd	202	nM	GILTERITINIB

PubChem BioAssay actives

3 with measured affinity, of 239 total; 3 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	2148187: Binding affinity to human CYC1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0006	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148187: Binding affinity to human CYC1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0293	uM
Gilteritinib	1424969: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2020	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	4
bisphenol A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
bisphenol S	increases expression, decreases expression	2
Doxorubicin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
bisphenol F	increases expression	1
moringin	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
pregna-4,17-diene-3,16-dione	affects localization	1
brequinar	affects expression	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	increases expression	1
corosolic acid	decreases expression	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases expression	1
Cannabidiol	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991682	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1UY	HAP1 CYC1 (-) 2	Cancer cell line	Male
CVCL_E1UZ	HAP1 CYC1 (-) 3	Cancer cell line	Male
CVCL_XN05	HAP1 CYC1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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