Thrombocytosis disease

Summary

Thrombocytosis disease (MONDO:0002249) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombocytosis disease
Mondo ID	MONDO:0002249
MeSH	D013922
DOID	DOID:2228
NCIT	C35530
SNOMED CT	6631009
UMLS	C0836924
MedGen	163397
Is cancer (heuristic)	no

Also known as: elevated Platelet count · Platelet count increased

Data availability: 5 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytosis disease

Related subtypes (4): inherited bleeding disorder, platelet-type, qualitative platelet defect, thrombocytopenia, TPM4-related platelet disorder

Subtypes (3): essential thrombocythemia, familial thrombocytosis, reactive thrombocytosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

5 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
975862	NM_018900.4(PCDHA1):c.2394+67303_2394+69956del	PCDHA4	Uncertain significance	criteria provided, single submitter
1685101	NM_005475.3(SH2B3):c.794G>A (p.Arg265Gln)	SH2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3440784	NM_005475.3(SH2B3):c.520G>A (p.Ala174Thr)	SH2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3574256	NM_005475.3(SH2B3):c.1696C>T (p.Arg566Trp)	SH2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3602706	NM_005475.3(SH2B3):c.632T>C (p.Met211Thr)	SH2B3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	clinvar
PCDHA4	HGNC:8670	ENSG00000204967	Q9UN74	Protocadherin alpha-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
PCDHA4	Protocadherin alpha-4	Calcium-dependent cell-adhesion protein involved in cells self-recognition and non-self discrimination.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
PCDHA4	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
cortical plate	1
islet of Langerhans	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
PCDHA4	96	broad	marker	cortical plate, stromal cell of endometrium, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SH2B3	1,617
PCDHA4	541

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PCDHA4	Q9UN74	74.23
SH2B3	Q9UQQ2	63.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 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
Negative regulation of FLT3	1	713.8×	0.008	SH2B3
Regulation of KIT signaling	1	601.0×	0.008	SH2B3
FLT3 Signaling	1	346.1×	0.010	SH2B3
Signaling by SCF-KIT	1	248.3×	0.010	SH2B3
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.030	SH2B3
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.032	SH2B3
Cytokine Signaling in Immune system	1	40.8×	0.035	SH2B3
Hemostasis	1	36.0×	0.035	SH2B3
Immune System	1	13.0×	0.086	SH2B3
Signal Transduction	1	10.2×	0.098	SH2B3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of Kit signaling pathway	1	4213.0×	0.003	SH2B3
monocyte homeostasis	1	2808.7×	0.003	SH2B3
negative regulation of receptor signaling pathway via STAT	1	1685.2×	0.003	SH2B3
cellular response to interleukin-3	1	1404.3×	0.003	SH2B3
negative regulation of response to cytokine stimulus	1	1404.3×	0.003	SH2B3
negative regulation of chemokine-mediated signaling pathway	1	1203.7×	0.003	SH2B3
thrombopoietin-mediated signaling pathway	1	1053.2×	0.003	SH2B3
neutrophil homeostasis	1	766.0×	0.003	SH2B3
negative regulation of platelet aggregation	1	702.2×	0.003	SH2B3
embryonic hemopoiesis	1	495.6×	0.004	SH2B3
cellular response to chemokine	1	495.6×	0.004	SH2B3
negative regulation of receptor signaling pathway via JAK-STAT	1	443.5×	0.004	SH2B3
hematopoietic stem cell differentiation	1	383.0×	0.004	SH2B3
megakaryocyte development	1	351.1×	0.004	SH2B3
erythrocyte development	1	263.3×	0.006	SH2B3
negative regulation of MAPK cascade	1	150.5×	0.009	SH2B3
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	131.7×	0.010	SH2B3
homophilic cell-cell adhesion	1	70.2×	0.017	PCDHA4
nervous system development	1	23.0×	0.050	PCDHA4
negative regulation of cell population proliferation	1	21.1×	0.052	SH2B3
intracellular signal transduction	1	19.1×	0.053	SH2B3
cell adhesion	1	18.7×	0.053	PCDHA4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SH2B3	0	0
PCDHA4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	SH2B3, PCDHA4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SH2B3	0	—
PCDHA4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.