Thrombocytopenia 4

Summary

Thrombocytopenia 4 (MONDO:0012775) is a disease caused by CYCS (GenCC Strong), with 1 cohort gene (29 GWAS associations across 5 studies) and 1 clinical trial.

At a glance

• Causal gene: CYCS (GenCC Strong)
• Cohort genes: 1
• GWAS associations: 29
• ClinVar variants: 15
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombocytopenia 4
Mondo ID	MONDO:0012775
MeSH	C567438
OMIM	612004
UMLS	C2677608
MedGen	394329
GARD	0018289
Is cancer (heuristic)	no

Also known as: CYCS thrombocytopenia · THC4 · thrombocytopenia 4 · thrombocytopenia caused by mutation in CYCS · thrombocytopenia type 4

Data availability: 15 ClinVar variants · 29 GWAS associations (5 studies) · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytopenia › inherited thrombocytopenia › thrombocytopenia 4

Related subtypes (20): thrombocytopenia 2, thrombocytopenia, cyclic, thrombocytopenia 3, congenital thrombotic thrombocytopenic purpura, thrombocytopenia, X-linked, with or without dyserythropoietic anemia, thrombocytopenia 1, thrombocytopenia 5, autosomal dominant macrothrombocytopenia, isolated delta-storage pool disease, syndromic constitutional thrombocytopenia, alpha granule disease, thrombocytopenia 7, macrothrombocytopenia, isolated, congenital autosomal recessive small-platelet thrombocytopenia, congenital amegakaryocytic thrombocytopenia, thrombocytopenia 9, thrombocytopenia 10, thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, thrombocytopenia 12 with or without myopathy, thrombocytopenia 13, syndromic

Genetics & variants

GWAS landscape

29 GWAS associations across 5 studies. Top hits map to 14 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs3747207	5e-43	PNPLA3	G	0.16
rs41303899	6e-35	TUBB1	G	1.09
rs77375493	3e-30	JAK2	G	1.47
rs1354034	2e-25	ARHGEF3	T	0.12
rs56043070	4e-24	GCSAML	G	0.19
rs6136493	5e-24	SIRPA - PDYN-AS1	A	0.11
rs73517714	6e-24	TPM4	C	0.24
rs74227709	7e-22	GCSAML	G	0.18
rs210140	2e-19	BAK1	C	0.09
rs6132105	1e-17	SIRPA - PDYN-AS1	G	0.09
chr19:16207232	1e-16		C	0.32
chr6:33547440	1e-16		G	0.09
rs6141	3e-16	THPO	C	0.08
chr2:43698753	4e-15		G	0.15
rs1331309	4e-15	HBS1L	T	0.09
rs7098181	4e-15	JMJD1C	G	0.08
rs113542380	3e-14	THADA	G	0.15
rs9402685	1e-13	HBS1L	T	0.08
rs10761731	2e-13	JMJD1C	A	0.08
rs187715179	3e-13	GTF3C5	C	0.44
rs17793951	1e-11	PPARG	A	0.07
rs2811708	1e-11	CDKN2A	G	0.08

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475809	Verma A	2024	19,555	417,795	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475808	Verma A	2024	4,335	114,134	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479983	Verma A	2024	4,335	114,134	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477466	Verma A	2024	2,318	56,054	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435822	Zhou W	2018	1,563	406,281	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	2
Tier 3: regulatory	0
Tier 4: intronic/intergenic	18

MAF distribution

Bucket	Variants
common (>=0.05)	18
low_freq (0.01-0.05)	1
rare (<0.01)	3
unknown	0

Functional consequences

Consequence	Count
intron_variant	11
intergenic_variant	4
unknown	3
missense_variant	2
splice_donor_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs3747207	22	43928975	G>A,C,T	0.219	intron_variant	PNPLA3	5e-43	Tier 4: intronic/intergenic
rs41303899	20	59023753	G>A	0.001	missense_variant	TUBB1	6e-35	Tier 1: coding
rs77375493	9	5073770	G>A,C,T	0	missense_variant	JAK2	3e-30	Tier 1: coding
rs1354034	3	56815721	T>C	0.497	intron_variant	ARHGEF3	2e-25	Tier 4: intronic/intergenic
rs56043070	1	247556467	G>A,T	0.061	splice_donor_variant	GCSAML	4e-24	Tier 2: splice/UTR
rs6136493	20	1943327	A>C,G,T	0.266	intergenic_variant	SIRPA - PDYN-AS1	5e-24	Tier 4: intronic/intergenic
rs73517714	19	16092494	C>A	0.034	intron_variant	TPM4	6e-24	Tier 4: intronic/intergenic
rs74227709	1	247559286	G>A	0.069	intron_variant	GCSAML	7e-22	Tier 4: intronic/intergenic
rs210140	6	33576516	C>T	0.392	intron_variant	BAK1	2e-19	Tier 4: intronic/intergenic
rs6132105	20	1943028	G>A,C	0.292	intergenic_variant	SIRPA - PDYN-AS1	1e-17	Tier 4: intronic/intergenic
chr19:16207232				0.076			1e-16	Tier 4: intronic/intergenic
chr6:33547440				0.389			1e-16	Tier 4: intronic/intergenic
rs6141	3	184372478	C>A,G,T	0.457	3_prime_UTR_variant	THPO	3e-16	Tier 2: splice/UTR
chr2:43698753				0.071			4e-15	Tier 4: intronic/intergenic
rs1331309	6	135085040	T>C,G	0.254	intergenic_variant	HBS1L	4e-15	Tier 4: intronic/intergenic
rs7098181	10	63267383	G>C,T	0.387	intron_variant	JMJD1C	4e-15	Tier 4: intronic/intergenic
rs113542380	2	43237679	G>A	0.058	intron_variant	THADA	3e-14	Tier 4: intronic/intergenic
rs9402685	6	135098550	T>C	0.252	intergenic_variant	HBS1L	1e-13	Tier 4: intronic/intergenic
rs10761731	10	63267850	A>C,G,T	0.421	intron_variant	JMJD1C	2e-13	Tier 4: intronic/intergenic
rs187715179	9	133044809	C>T	0.007	intron_variant	GTF3C5	3e-13	Tier 4: intronic/intergenic
rs17793951	3	12329238	A>G	0.321	intron_variant	PPARG	1e-11	Tier 4: intronic/intergenic
rs2811708	9	21973423	G>A,T	0.248	intron_variant	CDKN2A	1e-11	Tier 4: intronic/intergenic

ClinVar germline variants

15 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 2 likely pathogenic, 2 pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1210164	NM_018947.6(CYCS):c.79C>T (p.His27Tyr)	CYCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180656	NM_018947.6(CYCS):c.145T>C (p.Tyr49His)	CYCS	Pathogenic	no assertion criteria provided
599385	NM_018947.6(CYCS):c.301_303del (p.Lys101del)	CYCS	Pathogenic	no assertion criteria provided
16917	NM_018947.6(CYCS):c.124G>A (p.Gly42Ser)	CYCS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703823	NM_018947.6(CYCS):c.290C>A (p.Ala97Asp)	CYCS	Likely pathogenic	criteria provided, single submitter
2628903	NM_018947.6(CYCS):c.295C>T (p.Leu99Phe)	CYCS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627298	NM_018947.6(CYCS):c.308C>T (p.Thr103Ile)	CYCS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032049	NM_018947.6(CYCS):c.170-3T>C	CYCS	Uncertain significance	criteria provided, single submitter
1676752	NM_018947.6(CYCS):c.97C>G (p.Leu33Val)	CYCS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1684430	NM_018947.6(CYCS):c.94A>C (p.Asn32His)	CYCS	Uncertain significance	no assertion criteria provided
1684432	NM_018947.6(CYCS):c.62T>G (p.Val21Gly)	CYCS	Uncertain significance	no assertion criteria provided
1684433	NM_018947.6(CYCS):c.59C>T (p.Thr20Ile)	CYCS	Uncertain significance	no assertion criteria provided
1708125	NM_018947.6(CYCS):c.292T>C (p.Tyr98His)	CYCS	Uncertain significance	criteria provided, single submitter
810076	NM_018947.6(CYCS):c.154G>A (p.Ala52Thr)	CYCS	Uncertain significance	criteria provided, multiple submitters, no conflicts
261063	NM_018947.6(CYCS):c.-6T>G	CYCS	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CYCS	Strong	Autosomal dominant	thrombocytopenia 4	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYCS	Orphanet:168629	Autosomal thrombocytopenia with normal platelets

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYCS	HGNC:19986	ENSG00000172115	P99999	Cytochrome c	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYCS	Cytochrome c	Electron carrier protein.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYCS	Other/Unknown	no		Cyt_c_1A/1B, Cyt_c-like_dom, Cyt_c-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	1
rectum	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYCS	257	ubiquitous	marker	mucosa of transverse colon, rectum, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYCS	403

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYCS	P99999	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of caspases through apoptosome-mediated cleavage	1	1903.3×	0.002	CYCS
Release of apoptotic factors from the mitochondria	1	1631.4×	0.002	CYCS
SMAC (DIABLO) binds to IAPs	1	1631.4×	0.002	CYCS
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	1631.4×	0.002	CYCS
Formation of apoptosome	1	1427.5×	0.002	CYCS
Regulation of the apoptosome activity	1	1038.2×	0.002	CYCS
Pyroptosis	1	423.0×	0.004	CYCS
Detoxification of Reactive Oxygen Species	1	300.5×	0.005	CYCS
Transcriptional activation of mitochondrial biogenesis	1	203.9×	0.007	CYCS
Cytoprotection by HMOX1	1	184.2×	0.007	CYCS
TP53 Regulates Metabolic Genes	1	129.8×	0.008	CYCS
Respiratory electron transport	1	95.2×	0.011	CYCS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial electron transport, ubiquinol to cytochrome c	1	1296.3×	0.003	CYCS
mitochondrial electron transport, cytochrome c to oxygen	1	766.0×	0.003	CYCS
execution phase of apoptosis	1	766.0×	0.003	CYCS
cellular respiration	1	432.1×	0.003	CYCS
intrinsic apoptotic signaling pathway	1	358.6×	0.003	CYCS
apoptotic signaling pathway	1	224.7×	0.004	CYCS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYCS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CYCS	10	Binding:10

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CYCS

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CYCS	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07026578	Not specified	ACTIVE_NOT_RECRUITING	Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the Thrombocytopenia THC4