CYCS

Summary

CYCS (cytochrome c, somatic, HGNC:19986) is a protein-coding gene on chromosome 7p15.3, encoding Cytochrome c (P99999). Electron carrier protein. It is a common-essential gene (DepMap: required in 91.6% of cancer cell lines).

This gene encodes a small heme protein that functions as a central component of the electron transport chain in mitochondria. The encoded protein associates with the inner membrane of the mitochondrion where it accepts electrons from cytochrome b and transfers them to the cytochrome oxidase complex. This protein is also involved in initiation of apoptosis. Mutations in this gene are associated with autosomal dominant nonsyndromic thrombocytopenia. Numerous processed pseudogenes of this gene are found throughout the human genome.

Source: NCBI Gene 54205 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thrombocytopenia 4 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 61 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 91.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_018947

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19986
Approved symbol	CYCS
Name	cytochrome c, somatic
Location	7p15.3
Locus type	gene with protein product
Status	Approved
Aliases	HCS, CYC
Ensembl gene	ENSG00000172115
Ensembl biotype	protein_coding
OMIM	123970
Entrez	54205

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000305786, ENST00000409409, ENST00000409764, ENST00000413447, ENST00000877224, ENST00000877225, ENST00000877226, ENST00000877227, ENST00000912017, ENST00000912018, ENST00000962279

RefSeq mRNA: 1 — MANE Select: NM_018947 NM_018947

CCDS: CCDS5393

Canonical transcript exons

ENST00000305786 — 3 exons

Exon	Start	End
ENSE00001147465	25123951	25124127
ENSE00001207041	25118656	25123849
ENSE00001584587	25125200	25125260

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 80.7320 / max 2038.7012, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83156	77.0616	1819
83157	3.6704	1446

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.16	gold quality
rectum	UBERON:0001052	99.08	gold quality
right atrium auricular region	UBERON:0006631	99.04	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.91	gold quality
gastrocnemius	UBERON:0001388	98.52	gold quality
muscle of leg	UBERON:0001383	98.39	gold quality
cardiac atrium	UBERON:0002081	98.34	gold quality
prefrontal cortex	UBERON:0000451	98.22	gold quality
apex of heart	UBERON:0002098	98.21	gold quality
colonic epithelium	UBERON:0000397	98.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.94	gold quality
heart left ventricle	UBERON:0002084	97.94	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.92	gold quality
transverse colon	UBERON:0001157	97.90	gold quality
anterior cingulate cortex	UBERON:0009835	97.87	gold quality
cortical plate	UBERON:0005343	97.80	gold quality
smooth muscle tissue	UBERON:0001135	97.67	gold quality
vermiform appendix	UBERON:0001154	97.63	gold quality
cardiac ventricle	UBERON:0002082	97.53	gold quality
islet of Langerhans	UBERON:0000006	97.23	gold quality
right frontal lobe	UBERON:0002810	97.20	gold quality
embryo	UBERON:0000922	97.13	gold quality
ganglionic eminence	UBERON:0004023	97.13	gold quality
heart	UBERON:0000948	97.08	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.79	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.78	gold quality
ventricular zone	UBERON:0003053	96.76	gold quality
monocyte	CL:0000576	96.65	gold quality
hypothalamus	UBERON:0001898	96.43	gold quality
leukocyte	CL:0000738	96.42	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-7	yes	1218.54
E-HCAD-8	yes	1139.34
E-MTAB-8410	yes	22.34
E-CURD-122	yes	21.79
E-CURD-88	yes	18.75
E-MTAB-6701	yes	8.85
E-MTAB-7316	yes	7.98
E-MTAB-8271	yes	6.72
E-CURD-89	no	1614.90
E-HCAD-5	no	1413.55
E-MTAB-8060	no	629.62
E-GEOD-125970	no	15.85
E-CURD-46	no	11.28
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CREB1, CTNNB1, ESRRA, NRF1, PPARGC1A, PRKAA1, SP1, TCF7L2

miRNA regulators (miRDB)

163 targeting CYCS, 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-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 91.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• galectin-3 is enriched in the mitochondria and prevents mitochondrial damage and cytochrome c release (PMID:11839755)
• non-rare allelic variants of the Cyt c protein are absent in the populations analyzed in this study (PMID:16934433)
• Mutation of human cytochrome c enhances the intrinsic apoptotic pathway and causes thrombocytopenia (PMID:18345000)
• MICS1 individually functions in mitochondrial morphology and cytochrome c release. (PMID:18417609)
• Serum cyto-c is a potent tumor marker as a predictor for malignant potential in several different types of cancer. (PMID:18825408)
• Both neurons and cancer cells strictly inhibit cytochrome c-mediated apoptosis by a mechanism dependent on glucose metabolism. (PMID:19029908)
• In 77 Italian patients with inherited thrombocytopenia and clinical and laboratory features similar to those of patients with the CYCS missense (Gly41Ser) mutation, no alterations of the open reading frame were identified. (PMID:19172527)
• there was no evidence of somatic mutations of CYTOCHROME C in the cancers (PMID:19404857)
• No difference in the serum level of cytochrome c was seen among the the groups of patients with type 2 diabetes, controls or in subjects with IGT. (PMID:19640329)
• Data show that sorafenib initiated lethal apoptotic process through the release of cytochrome c and caspase 3/7 activation. (PMID:19770576)
• Serum LRG when bound to extracellular Cyt c that is released from apoptotic cells acts as a survival factor for lymphocytes and possibly other cells that are susceptible to the toxic effect of extracellular Cyt c. (PMID:19851871)
• Membrane-associated XIAP induces mitochondrial outer membrane permeabilization leading to cytochrome c and Smac release, which is dependent on Bax and Bak. (PMID:19875445)
• NOA36/ZNF330 is translocated from the mitochondria to the cytoplasm when apoptosis is induced and that it contributes to cytochrome c release. (PMID:19895853)
• it is the specific nitration of solvent-exposed Tyr74 which enhances the peroxidase activity and blocks the ability of cytochrome c to activate caspase-9, thereby preventing the apoptosis signaling pathway (PMID:20227384)
• heme electronic structure change may ultimately be responsible for the enhanced proapoptotic activity of G41S mutated human cyt c (PMID:21192676)
• Cerebrospinal fluid Bcl-2 and cytochrome C levels are elevated in adults after severe traumatic brain injury. (PMID:21448217)
• Tyrosine phosphorylation turns alkaline transition into a biologically relevant process and makes human cytochrome c behave as an anti-apoptotic switch. (PMID:21706253)
• Resveratrol induces p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated Bax protein oligomerization on mitochondria to initiate cytochrome c release and caspase activation. (PMID:21712378)
• Data show that G-Rh2 and Bet A cooperated to induce Bax traslocation to mitochondria and cytochrome c release, and enhanced cleavage of caspase-8 and Bid. (PMID:21751259)
• Translocation of ARTS initiates a first wave of caspase activation leading to the subsequent release of additional mitochondrial factors, including cytochrome C and SMAC/Diablo. (PMID:21869827)
• Studies indicate that the CYCS mutation in TP Cargeegis a glycine 41 replacement by serine, which yields a cytochrome C variant with enhanced apoptotic pathway activity in vitro. (PMID:22102269)
• mitochondrial import and direct electron transfer from cytochrome c to Rac1 modulates mitochondrial H(2)O(2) production in alveolar macrophages pulmonary fibrosis. (PMID:22157762)
• Dynamic changes in cytochrome c distribution at the Raman band of 750 cm(-1) were observed after adding an apoptosis inducer to the cells. (PMID:22184220)
• Specific nitration of tyrosines 46 and 48 makes cytochrome c assemble a non-functional apoptosome. (PMID:22192356)
• The levels of cellular apoptosis-associated proteins such as Smac/DIABLO, Cyto C, and the activated fragment of caspase-3 increased in pancreatic cancer cells, but the expression of XIAP was significantly decreased after 24 h treatment with the combination of TRAIL and gemcitabine. (PMID:22320973)
• CCN1 promotes the activation of p53 and p38 MAPK, which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFalpha. (PMID:22363611)
• structural characterization of cytochrome c in micelle (PMID:23070294)
• Spectroscopic analyses of HCCS alone and complexes of HCCS with site-directed variants of cytochrome c revealed the fundamental steps of heme attachment and maturation. (PMID:23150584)
• Data indicate that the formation of cytochrome c-Apaf-1 apoptosome and the presence of Smac are absolutely required for PSAP-induced apoptosis. (PMID:23207240)
• results suggest the impact of residue 41 on the conformation of cytochrome c influences its ability to act in both of its physiological roles, electron transport and caspase activation (PMID:23334161)
• G-Rh2 causes rapid and dramatic translocation of both Bak and Bax, which subsequently triggers mitochondrial cytochrome c release and consequent caspase activation. (PMID:23443079)
• a mechanism of multiple radical formations in the cytochrome c-phospholipid complexes under H2O2 treatment, consistent with the stabilization of the radical in the G41S mutant, which elicits a greater peroxidase activity from cytochrome c (PMID:24099549)
• Data indicate a novel missense mutation (Y48H) of the cytochrome c (CYCS) gene responsible for thrombocytopenia. (PMID:24326104)
• proposed that mutation of residue 41, and interaction with cardiolipin, increase peroxidase activity by altering the 40-57 Omega loop and its hydrogen bond network with the propionate of haem ring A; these changes enhance access of hydrogen peroxide and substrate to the haem (PMID:24329121)
• In vitro ultrastructural changes of MCF-7 for metastasise bone cancer and induction of apoptosis via mitochondrial cytochrome C released by CaCO3/Dox nanocrystals (PMID:25028650)
• The mitochondrial metalloprotease OMA1 was activated in a Bax- and Bak-dependent fashion. (PMID:25275009)
• Monitoring of serum cytochrome c might also serve as a sensitive apoptotic marker in vivo reflecting chemotherapy-induced cell death burden in patients with non-small cell lung cancer. (PMID:25578497)
• These findings establish a framework for understanding the molecular basis of cytochrome c-mediated blocking of SET/TAF-Ibeta. (PMID:26216969)
• This work reveals a direct conformational link between the 40-57 Omega-loop of cytochrome c in which residue 41 resides and the dynamical properties of the axial ligand to the heme iron. (PMID:27461282)
• ROCK activation phosphorylated Rac1b at Ser71 and increased reactive oxygen species (ROS) levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation abolished their interaction, concomitant with ROS reduction. (PMID:28317242)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gm10053	ENSMUSG00000058927
mus_musculus	Cycs	ENSMUSG00000063694
rattus_norvegicus	Cycs	ENSRNOG00000010452
rattus_norvegicus	AC128290.1	ENSRNOG00000033559
rattus_norvegicus	Cycs-ps9	ENSRNOG00000065095
drosophila_melanogaster	Cyt-c-d	FBGN0086907
caenorhabditis_elegans		WBGENE00013854
caenorhabditis_elegans		WBGENE00017121

Protein

Protein identifiers

Cytochrome c — P99999 (reviewed: P99999)

All UniProt accessions (3): P99999, C9JFR7, G4XXL9

UniProt curated annotations — full annotation on UniProt →

Function. Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain. Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases.

Subcellular location. Mitochondrion intermembrane space.

Post-translational modifications. Binds 1 heme c group covalently per subunit. Phosphorylation at Tyr-49 and Tyr-98 both reduce by half the turnover in the reaction with cytochrome c oxidase, down-regulating mitochondrial respiration.

Disease relevance. Thrombocytopenia 4 (THC4) [MIM:612004] A form of thrombocytopenia, a hematologic disorder defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the cytochrome c family.

RefSeq proteins (1): NP_061820* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002327	Cyt_c_1A/1B	Family
IPR009056	Cyt_c-like_dom	Domain
IPR036909	Cyt_c-like_dom_sf	Homologous_superfamily

Pfam: PF00034

UniProt features (36 total): modified residue 7, mutagenesis site 6, helix 5, strand 5, binding site 4, sequence variant 3, sequence conflict 2, turn 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
5TY3	X-RAY DIFFRACTION	1.25
3ZOO	X-RAY DIFFRACTION	1.35
5O10	X-RAY DIFFRACTION	1.36
5EXQ	X-RAY DIFFRACTION	1.6
3ZCF	X-RAY DIFFRACTION	1.65
6DUJ	X-RAY DIFFRACTION	1.82
3NWV	X-RAY DIFFRACTION	1.9
6XNK	X-RAY DIFFRACTION	2.08
6ECJ	X-RAY DIFFRACTION	2.7
1J3S	SOLUTION NMR
2N3Y	SOLUTION NMR
2N9I	SOLUTION NMR
2N9J	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P99999-F1	97.95	0.98

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): 15 (covalent); 18 (covalent); 19 (axial binding residue); 81 (axial binding residue)

Post-translational modifications (7): 73, 98, 100, 2, 49, 56, 73

Mutagenesis-validated functional residues (6):

Position	Phenotype
6	no effect on covalent heme attachment.
11	decreased covalent heme attachment.
11	no effect on covalent heme attachment.
15	decreased covalent heme attachment.
18	decreased covalent heme attachment.
19	loss of covalent heme attachment.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-111457	Release of apoptotic factors from the mitochondria
R-HSA-111458	Formation of apoptosome
R-HSA-111459	Activation of caspases through apoptosome-mediated cleavage
R-HSA-111463	SMAC (DIABLO) binds to IAPs
R-HSA-111464	SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-5620971	Pyroptosis
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-611105	Respiratory electron transport
R-HSA-9627069	Regulation of the apoptosome activity
R-HSA-9707564	Cytoprotection by HMOX1

MSigDB gene sets: 319 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, MODULE_93, MORF_ESPL1, WWTAAGGC_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MORF_BUB1, BASSO_B_LYMPHOCYTE_NETWORK, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MORF_UBE2N, DITTMER_PTHLH_TARGETS_UP, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, KYNG_DNA_DAMAGE_DN, MORF_HDAC2, RODWELL_AGING_KIDNEY_NO_BLOOD_DN

GO Biological Process (7): mitochondrial electron transport, ubiquinol to cytochrome c (GO:0006122), mitochondrial electron transport, cytochrome c to oxygen (GO:0006123), cellular respiration (GO:0045333), apoptotic signaling pathway (GO:0097190), intrinsic apoptotic signaling pathway (GO:0097193), execution phase of apoptosis (GO:0097194), apoptotic process (GO:0006915)

GO Molecular Function (4): electron transfer activity (GO:0009055), heme binding (GO:0020037), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), cytosol (GO:0005829), apoptosome (GO:0043293)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Cytochrome c-mediated apoptotic response	2
SMAC, XIAP-regulated apoptotic response	2
Cellular response to chemical stress	2
Apoptotic factor-mediated response	1
Mitochondrial biogenesis	1
Regulated Necrosis	1
Transcriptional Regulation by TP53	1
Aerobic respiration and respiratory electron transport	1
Formation of apoptosome	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aerobic electron transport chain	2
mitochondrial ATP synthesis coupled electron transport	2
apoptotic process	2
apoptotic signaling pathway	2
intracellular membrane-bounded organelle	2
cytoplasm	2
energy derivation by oxidation of organic compounds	1
signal transduction	1
intracellular signal transduction	1
cellular process	1
bleb assembly	1
programmed cell death	1
execution phase of apoptosis	1
molecular_function	1
tetrapyrrole binding	1
cation binding	1
binding	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial envelope	1
organelle envelope lumen	1
cellular anatomical structure	1
cytosol	1
protein-containing complex	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

192 interactions, top by confidence:

A	B	Type	Score
APAF1	CASP9	psi-mi:“MI:0914”(association)	0.960
APAF1	CASP9	psi-mi:“MI:0915”(physical association)	0.960
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
KRT40	CYCS	psi-mi:“MI:0915”(physical association)	0.720
CYCS	KRT40	psi-mi:“MI:0915”(physical association)	0.720
APAF1	CYCS	psi-mi:“MI:0915”(physical association)	0.690
CYCS	APAF1	psi-mi:“MI:0915”(physical association)	0.690
LRG1	CYCS	psi-mi:“MI:0914”(association)	0.620
LRG1	CYCS	psi-mi:“MI:0915”(physical association)	0.620
CYCS	CYC1-2	psi-mi:“MI:0407”(direct interaction)	0.560
CYC1-2	CYCS	psi-mi:“MI:0407”(direct interaction)	0.560
CYCS	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
CYCS	FYN	psi-mi:“MI:0915”(physical association)	0.560
ZBTB14	CYCS	psi-mi:“MI:0915”(physical association)	0.560
CYCS	SYMPK	psi-mi:“MI:0915”(physical association)	0.560
EIF3F	CYCS	psi-mi:“MI:0915”(physical association)	0.560
SNW1	CYCS	psi-mi:“MI:0915”(physical association)	0.560
BRWD1	CYCS	psi-mi:“MI:0915”(physical association)	0.560
CROT	CYCS	psi-mi:“MI:0915”(physical association)	0.560
CYCS	SEMA4G	psi-mi:“MI:0915”(physical association)	0.560
CYCS	MLST8	psi-mi:“MI:0915”(physical association)	0.560
COA7	CYCS	psi-mi:“MI:0915”(physical association)	0.560
PHF23	CYCS	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (211): CYCS (Co-fractionation), KRT40 (Two-hybrid), CYCS (Affinity Capture-Western), CYCS (Biochemical Activity), ACAT1 (Co-fractionation), CYCS (Co-fractionation), CYCS (Co-fractionation), CYCS (Co-fractionation), CYCS (Co-fractionation), CYCS (Co-fractionation), GLRX2 (Co-fractionation), IMPA1 (Co-fractionation), IMPA2 (Co-fractionation), NLE1 (Co-fractionation), CYCS (Affinity Capture-MS)

ESM2 similar proteins: B4USV4, P00002, P00004, P00007, P00008, P00011, P00012, P00013, P00014, P00015, P00017, P00018, P00019, P00020, P00021, P00022, P00024, P00028, P00029, P10715, P21665, P62894, P62895, P62896, P62897, P62898, P67881, P67882, P68096, P68097, P68098, P68099, P68100, P68517, P68518, P68519, P81280, P99998, P99999, Q4SG99

Diamond homologs: A2Y4S9, B4USV4, O22642, O23138, P00002, P00003, P00004, P00007, P00008, P00011, P00012, P00013, P00014, P00015, P00017, P00018, P00019, P00020, P00021, P00022, P00025, P00026, P00028, P00035, P00036, P00037, P00038, P00039, P00040, P00046, P00047, P00048, P00051, P00052, P00053, P00054, P00056, P00057, P00058, P00059

SIGNOR signaling

28 interactions.

A	Effect	B	Mechanism
BAK1	up-regulates	CYCS	relocalization
CYCS	“up-regulates activity”	APAF1	binding
TP53	up-regulates	CYCS
PRKAA1	“up-regulates quantity by expression”	CYCS	“transcriptional regulation”
BAK1	up-regulates	CYCS
BAX	up-regulates	CYCS
PINK1	“down-regulates quantity”	CYCS
“Caspase 8 complex”	“up-regulates activity”	CYCS
3a	“up-regulates activity”	CYCS
GHITM	“down-regulates quantity”	CYCS	relocalization
“CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III”	“up-regulates activity”	CYCS	“chemical modification”
CYCS	“up-regulates activity”	“Cytochrome c oxidase-Mitochondrial respiratory chain complex IV”
HCCS	“up-regulates activity”	CYCS	“chemical modification”
“heme b”	“up-regulates activity”	CYCS	“chemical modification”
CYCS	“up-regulates activity”	CASP9	binding
BID	“up-regulates activity”	CYCS
CASP8	“up-regulates activity”	CYCS
BAX	up-regulates	CYCS	relocalization
BCL2	“down-regulates activity”	CYCS
PPARGC1A	“up-regulates quantity by expression”	CYCS	“transcriptional regulation”
CYCS	up-regulates	Oxidative_phosphorylation
CYCS	“form complex”	Apoptosome	binding
AKT3	“down-regulates activity”	CYCS	phosphorylation
AKT2	“down-regulates activity”	CYCS	phosphorylation
AKT1	“down-regulates activity”	CYCS	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 146 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
Processing of SMDT1	5	32.7×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of apoptotic process	16	4.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	26
Likely benign	18
Benign	1

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
180656	NM_018947.6(CYCS):c.145T>C (p.Tyr49His)	Pathogenic
599385	NM_018947.6(CYCS):c.301_303del (p.Lys101del)	Pathogenic
16917	NM_018947.6(CYCS):c.124G>A (p.Gly42Ser)	Likely pathogenic
1703823	NM_018947.6(CYCS):c.290C>A (p.Ala97Asp)	Likely pathogenic
812966	NM_018947.6(CYCS):c.295C>G (p.Leu99Val)	Likely pathogenic

SpliceAI

485 predictions. Top by Δscore:

Variant	Effect	Δscore
7:25123703:A:AC	donor_gain	1.0000
7:25123704:C:CC	donor_gain	1.0000
7:25123707:A:AC	donor_gain	1.0000
7:25123708:T:C	donor_gain	1.0000
7:25123714:G:C	donor_gain	1.0000
7:25123742:C:A	donor_gain	1.0000
7:25123750:T:TA	donor_gain	1.0000
7:25123751:C:A	donor_gain	1.0000
7:25123754:T:TA	donor_gain	1.0000
7:25123761:AATG:A	donor_gain	1.0000
7:25123799:T:TA	donor_gain	1.0000
7:25123847:TGCCT:T	acceptor_loss	1.0000
7:25123848:GCCTA:G	acceptor_loss	1.0000
7:25123849:CCTA:C	acceptor_loss	1.0000
7:25123850:C:A	acceptor_loss	1.0000
7:25123850:C:CC	acceptor_gain	1.0000
7:25123851:T:G	acceptor_loss	1.0000
7:25123945:TCTTA:T	donor_loss	1.0000
7:25123947:TTAC:T	donor_loss	1.0000
7:25123948:TA:T	donor_loss	1.0000
7:25124123:TAATT:T	acceptor_gain	1.0000
7:25124124:AATTC:A	acceptor_loss	1.0000
7:25124126:TT:T	acceptor_gain	1.0000
7:25124127:TC:T	acceptor_loss	1.0000
7:25124128:C:CA	acceptor_loss	1.0000
7:25124128:C:CC	acceptor_gain	1.0000
7:25125195:CTCA:C	donor_loss	1.0000
7:25125196:TCA:T	donor_loss	1.0000
7:25125197:CACCT:C	donor_loss	1.0000
7:25125198:A:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000642175 (7:25126282 C>T), RS1000873227 (7:25120666 C>G), RS1000923842 (7:25126477 C>A,T), RS1001354090 (7:25125740 T>C), RS1001463180 (7:25125129 G>A), RS1001548451 (7:25120970 C>G), RS1001553120 (7:25120874 C>T), RS1001761643 (7:25125870 A>G), RS1001970856 (7:25122225 TCA>T), RS1002205276 (7:25121195 G>A,C), RS1002254692 (7:25121081 G>A,T), RS1002593044 (7:25122038 C>A,G,T), RS1003427715 (7:25127018 G>A,C), RS1003571394 (7:25123438 T>C), RS1003905452 (7:25124748 A>G)

Disease associations

OMIM: gene MIM:123970 | disease phenotypes: MIM:612004

GenCC curated gene-disease

Disease	Classification	Inheritance
thrombocytopenia 4	Strong	Autosomal dominant
autosomal thrombocytopenia with normal platelets	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
thrombocytopenia 4	Limited	AD

Mondo (3): thrombocytopenia 4 (MONDO:0012775), thrombocytopenia (MONDO:0002049), (MONDO:0015679)

Orphanet (1): Hereditary thrombocytopenia with normal platelets (Orphanet:268322)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001873	Thrombocytopenia
HP:0011876	Abnormal platelet volume

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001915_19	Alzheimer’s disease (cognitive decline)	2.000000e-07
GCST004867_20	Systemic lupus erythematosus	2.000000e-06
GCST007202_17	High density lipoprotein cholesterol levels	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C567438	Thrombocytopenia 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2189163 (SINGLE PROTEIN), CHEMBL3885517 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 12 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.97	Kd	107.3	nM	CHEMBL5653589
6.97	ED50	107.3	nM	CHEMBL5653589
6.02	Kd	950	nM	CHEMBL353314
5.82	Kd	1500	nM	CHEMBL385913
5.77	Kd	1700	nM	CHEMBL1213293

PubChem BioAssay actives

4 with measured affinity, of 76 total; 4 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148188: Binding affinity to human CYCS incubated for 45 mins by Kinobead based pull down assay	kd	0.1073	uM
4-[10,15,20-tris(4-carboxyphenyl)-21,24-dihydroporphyrin-5-yl]benzoic acid	495781: Binding affinity to Cytochrome C	kd	0.9500	uM
5-[4-[10,15,20-tris[4-(3,5-dicarboxyphenyl)phenyl]-21,24-dihydroporphyrin-5-yl]phenyl]benzene-1,3-dicarboxylic acid	495781: Binding affinity to Cytochrome C	kd	1.5000	uM
(3S)-3-[[3-[[(2S)-3-carboxy-1-methoxy-1-oxopropan-2-yl]carbamoyl]-5-[4-[10,15,20-tris[4-[3,5-bis[[(2S)-3-carboxy-1-methoxy-1-oxopropan-2-yl]carbamoyl]phenyl]phenyl]-21,23-dihydroporphyrin-5-yl]phenyl]benzoyl]amino]-4-methoxy-4-oxobutanoic acid	495781: Binding affinity to Cytochrome C	kd	1.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases reaction, affects reaction, increases expression, increases reaction, affects cotreatment (+1 more)	15
Doxorubicin	affects cotreatment, increases expression, decreases reaction, increases reaction, affects response to substance (+2 more)	12
Acetylcysteine	affects localization, decreases reaction, increases expression, decreases expression	8
Quercetin	increases reaction, affects cotreatment, affects expression, affects localization, increases expression (+1 more)	8
Paclitaxel	increases expression, increases secretion, affects cotreatment, affects localization	8
sodium arsenite	increases reaction, decreases reaction, increases expression, affects localization, decreases expression (+2 more)	7
Cisplatin	affects cotreatment, increases expression, affects expression, affects localization, decreases expression	7
Plant Extracts	increases abundance, increases expression, affects localization, decreases reaction, decreases expression	7
Copper	increases activity, increases metabolic processing, increases reaction, affects binding, increases expression (+2 more)	6
Valproic Acid	affects cotreatment, increases expression, affects expression	6
bisphenol A	affects expression, decreases expression, increases expression, increases methylation, decreases reaction	5
Arsenic Trioxide	affects cotreatment, increases expression, affects localization, increases secretion, increases reaction	5
Cadmium	increases expression, affects cotreatment, decreases reaction, increases abundance, increases palmitoylation (+2 more)	5
Estradiol	affects reaction, increases expression, affects localization, decreases reaction	5
Cadmium Chloride	increases expression, decreases reaction, increases abundance, increases palmitoylation, affects localization (+1 more)	5
Cannabidiol	increases expression, decreases reaction, decreases expression, affects cotreatment	4
Tamoxifen	affects localization, decreases reaction, affects cotreatment, affects expression, increases expression	4
hydroquinone	decreases reaction, increases expression, affects localization	3
alvocidib	decreases reaction, affects localization, affects cotreatment	3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects localization, decreases reaction, increases expression	3
pterostilbene	affects localization, increases expression	3
pyrazolanthrone	decreases reaction, increases expression, affects localization, increases reaction	3
Troglitazone	affects localization, decreases activity, decreases reaction, decreases expression, increases expression (+1 more)	3
Curcumin	increases expression, affects localization, affects binding, affects cotreatment	3
Drugs, Chinese Herbal	affects localization, increases expression	3
Glucose	decreases reaction, increases expression, affects cotreatment	3
Nitric Oxide	affects localization, decreases secretion	3
Oxygen	increases reaction, affects expression, affects reaction, decreases expression, decreases reaction (+1 more)	3
Paraquat	affects cotreatment, decreases reaction, increases expression, affects localization	3
Smoke	decreases expression, increases abundance, affects localization	3

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1218067	Binding	Binding affinity to Cytochrome C	A novel class of meso-tetrakis-porphyrin derivatives exhibits potent activities against hepatitis C virus genotype 1b replicons in vitro. — Antimicrob Agents Chemother

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count
NCT07442513	PHASE3	RECRUITING	Comparison of Etamsylate Versus Placebo to Prevent Bleeding in HSCT