CYCS

Chr 7

cytochrome c, somatic

Also known as: CYC, HCS, THC4

NCBI Gene: 54205ENSG00000172115UniProt: P99999

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.[provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

UniProtThrombocytopenia 4
86
ClinVar variants
39
Pathogenic / LP
0.64
pLI score
6
Active trials
Clinical Summary— CYCS
🧬
Gene-Disease Validity (ClinGen)
thrombocytopenia 4 · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.64) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
39 Pathogenic / Likely Pathogenic· 27 VUS of 86 total submissions
💊
Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.91LOEUF
pLI 0.636
Z-score 1.67
OE 0.00 (0.00–0.91)
Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.18Z-score
OE missense 0.55 (0.41–0.74)
30 obs / 54.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.91)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.41–0.74)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.31
0≤1.21.6
LoF obs/exp: 0 / 3.2Missense obs/exp: 30 / 54.6Syn Z: -1.07

ClinVar Variant Classifications

86 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic8
VUS27
Likely Benign18
Benign1
Conflicting1
31
Pathogenic
8
Likely Pathogenic
27
VUS
18
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
30
0
31
Likely Pathogenic
0
5
3
0
8
VUS
1
20
6
0
27
Likely Benign
0
0
5
13
18
Benign
0
0
1
0
1
Conflicting
—1
Total126451386

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CYCS · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — CYCS
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Copper metabolism in cell death and autophagy.
Xue Q et al.·Autophagy
2023Review
Preclinical Alzheimer's disease shows alterations in circulating neuronal-derived extracellular vesicle microRNAs in a multiethnic cohort.
Reho P et al.·Alzheimers Dement
2025Cohort
Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.
Zhu Y et al.·Autophagy
2025
Respiratory toxicity mechanism of 6PPD and 6PPD-quinone: An integrated study based on network toxicology and molecular docking.
Li G et al.·Ecotoxicol Environ Saf
2025Functional
Exploring the mechanism of ellagic acid against gastric cancer based on bioinformatics analysis and network pharmacology.
Liu Z et al.·J Cell Mol Med
2023Functional
Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
Chung CY et al.·Autophagy
2025
[Role of CYCS in the cytogenesis and apoptosis of male germ cells and its clinical application].
Liang YD et al.·Zhonghua Nan Ke Xue
2020Review
The Identification and Clinical Value Evaluation of CYCS Related to Asthma through Bioinformatics Analysis and Functional Experiments.
Li Y et al.·Dis Markers
2023Functional
Target oxidative stress-induced disulfidptosis: novel therapeutic avenues in Parkinson's disease.
Zhang J et al.·Mol Brain
2025
A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation study.
Štika J et al.·Br J Haematol
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Thrombocytopenia, IsolatedThrombocytopenia 4CYCS MUTATION- ASSOCIATED THROMBOCYTOPENIA THC4

Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the Thrombocytopenia THC4

ACTIVE NOT RECRUITING
NCT07026578Fondazione IRCCS Policlinico San Matteo di PaviaStarted 2024-06-18
Blood draw for the laboratory assessment
Diabetes (DM)Diabetic KetoacidosisKetosis Prone Diabetes

Phase 1 Trial of Arginine Hydrochloride for the Management of Diabetic Ketoacidosis in Type 2 Diabetes

RECRUITING
NCT07167693Phase PHASE1, PHASE2David K CarrollStarted 2025-12-19
Arginine hydrochlorideSodium Chloride 0.9%
Schizophrenia and Related DisordersMitochondrial AlterationCognitive Impairment

MitoQ for Early-phase Schizophrenia-spectrum Disorder and Mitochondrial Dysfunction

RECRUITING
NCT06191965Phase PHASE2, PHASE3Mclean HospitalStarted 2024-06-01
MitoQPlacebo
Cardiomyopathy Due to Drug

Myocardial Fibrosis Identification in Patients With Anthracycline-induced Cardiotoxicity

RECRUITING
NCT06331806Phase NAEuropean Institute of OncologyStarted 2018-02-22
Evaluation of myocardial fibrosis
Chronic Granulomatous Disease (CGD)

Part B- G1X-CGD (Lentiviral Vector Transduced CD34+ Cells) in Patients With X-Linked Chronic Granulomatous Disease

ENROLLING BY INVITATION
NCT07113743Phase PHASE1, PHASE2National Institute of Allergy and Infectious Diseases (NIAID)Started 2025-09-10
BusulfanTocilizumabEltrombopag
Aortic Aneurysm and Dissection

MITAORTA - Role of Mitochondrial Dynamic in Aneurysm and Dissection of Ascending Thoracic Aorta

ACTIVE NOT RECRUITING
NCT05434481Phase NAUniversity Hospital, AngersStarted 2022-09-07
Mitochondrial dynamic analysis in the aorta samples and metabolomic profiling in the aortic diseases

External Resources

Links to major genomics databases and tools