Platelet-type bleeding disorder 19

Summary

Platelet-type bleeding disorder 19 (MONDO:0014518) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	platelet-type bleeding disorder 19
Mondo ID	MONDO:0014518
OMIM	616176
Orphanet	438207
DOID	DOID:0111048
UMLS	C4015405
MedGen	863842
GARD	0017738
Is cancer (heuristic)	no

Also known as: BDPLT19 · bleeding disorder, platelet-type, 19 · isolated hereditary giant platelet disorder caused by mutation in PRKACG · PRKACG isolated hereditary giant platelet disorder · severe autosomal recessive macrothrombocytopenia

Data availability: 1 ClinVar variant · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › hemorrhagic disease › inherited bleeding disorder, platelet-type › platelet-type bleeding disorder 19

Related subtypes (27): gray platelet syndrome, primary release disorder of platelets, platelet-type von Willebrand disease, platelet-type bleeding disorder 16, platelet-type bleeding disorder 17, Ehlers-Danlos syndrome, fibronectinemic type, Bernard-Soulier syndrome, Scott syndrome, congenital thrombotic thrombocytopenic purpura, Quebec platelet disorder, platelet-type bleeding disorder 12, platelet-type bleeding disorder 10, platelet-type bleeding disorder 8, platelet-type bleeding disorder 14, platelet-type bleeding disorder 9, platelet-type bleeding disorder 11, platelet-type bleeding disorder 15, platelet-type bleeding disorder 18, platelet-type bleeding disorder 20, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder, bleeding disorder, platelet-type, 24, bleeding disorder, platelet-type, 22, bleeding disorder, platelet-type, 21, Glanzmann thrombasthenia, bleeding diathesis due to thromboxane synthesis deficiency, bleeding disorder, platelet-type, 25

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

1 retrieved; paginated sample, class counts are floors:

1 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
162394	NM_002732.4(PRKACG):c.222C>G (p.Ile74Met)	PRKACG	no classifications from unflagged records	no classifications from unflagged records

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 4 · 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
GNE	Supportive	Autosomal recessive	platelet-type bleeding disorder 19	13
PRKACG	Supportive	Autosomal recessive	platelet-type bleeding disorder 19	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKACG	Orphanet:438207	Severe autosomal recessive macrothrombocytopenia
GNE	Orphanet:3166	Sialuria
GNE	Orphanet:438207	Severe autosomal recessive macrothrombocytopenia
GNE	Orphanet:602	GNE myopathy

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
PRKACG	HGNC:9382	ENSG00000165059	P22612	cAMP-dependent protein kinase catalytic subunit gamma	gencc,clinvar
GNE	HGNC:23657	ENSG00000159921	Q9Y223	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKACG	cAMP-dependent protein kinase catalytic subunit gamma	Phosphorylates a large number of substrates in the cytoplasm and the nucleus.
GNE	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	Bifunctional enzyme that possesses both UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities, and serves as the initiator of the biosynthetic pathway leading to the production of N-acetylneuraminic acid (NeuAc), a…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKACG	Kinase	yes	2.7.11.11	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
GNE	Enzyme (other)	yes	2.7.1.60	ROK, UDP_GlcNAc_Epimerase_2_dom, UDP-GlcNAc_Epase

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)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
male germ cell	1
sperm	1
colonic mucosa	1
mucosa of sigmoid colon	1
nasal cavity epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKACG	17	tissue_specific	yes	sperm, male germ cell, left testis
GNE	286	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, nasal cavity epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKACG	6,817
GNE	2,210

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNE	Q9Y223	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKACG	P22612	94.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 81. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GNE causes sialuria, NK and IBM2	1	5710.0×	0.014	GNE
PKA-mediated phosphorylation of key metabolic factors	1	1142.0×	0.017	PRKACG
HDL assembly	1	713.8×	0.017	PRKACG
ROBO receptors bind AKAP5	1	634.4×	0.017	PRKACG
Regulation of glycolysis by fructose 2,6-bisphosphate metabolism	1	475.8×	0.017	PRKACG
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	439.2×	0.017	PRKACG
Glucose metabolism	1	439.2×	0.017	PRKACG
Rap1 signalling	1	356.9×	0.017	PRKACG
Plasma lipoprotein assembly	1	356.9×	0.017	PRKACG
PKA activation in glucagon signalling	1	335.9×	0.017	PRKACG
Triglyceride metabolism	1	335.9×	0.017	PRKACG
PKA activation	1	317.2×	0.017	PRKACG
PKA-mediated phosphorylation of CREB	1	285.5×	0.017	PRKACG
CD209 (DC-SIGN) signaling	1	259.6×	0.017	PRKACG
Triglyceride catabolism	1	237.9×	0.017	PRKACG
DARPP-32 events	1	237.9×	0.017	PRKACG
Anti-inflammatory response favouring Leishmania parasite infection	1	196.9×	0.017	PRKACG
Leishmania parasite growth and survival	1	196.9×	0.017	PRKACG
Calmodulin induced events	1	190.3×	0.017	PRKACG
CaM pathway	1	190.3×	0.017	PRKACG
Ca-dependent events	1	184.2×	0.017	PRKACG
Aquaporin-mediated transport	1	184.2×	0.017	PRKACG
Glucagon signaling in metabolic regulation	1	173.0×	0.017	PRKACG
G-protein mediated events	1	163.1×	0.017	PRKACG
Sialic acid metabolism	1	163.1×	0.017	GNE
DAG and IP3 signaling	1	158.6×	0.017	PRKACG
Response of endothelial cells to shear stress	1	150.3×	0.017	PRKACG
FCGR3A-mediated IL10 synthesis	1	146.4×	0.017	PRKACG
Glycolysis	1	142.8×	0.017	PRKACG
Opioid Signalling	1	132.8×	0.017	PRKACG

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
N-acetylglucosamine biosynthetic process	1	4213.0×	0.002	GNE
N-acetylneuraminate biosynthetic process	1	2808.7×	0.002	GNE
UDP-N-acetylglucosamine metabolic process	1	1404.3×	0.002	GNE
CMP-N-acetylneuraminate biosynthetic process	1	1404.3×	0.002	GNE
high-density lipoprotein particle assembly	1	842.6×	0.003	PRKACG
vascular endothelial cell response to laminar fluid shear stress	1	366.4×	0.005	PRKACG
renal water homeostasis	1	255.3×	0.006	PRKACG
positive regulation of insulin secretion	1	127.7×	0.011	PRKACG
male gonad development	1	78.0×	0.016	PRKACG
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.019	PRKACG
spermatogenesis	1	17.6×	0.056	PRKACG

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PRKACG	ALPELISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKACG	10	4
GNE	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALPELISIB	4	PRKACG
FASUDIL	3	PRKACG
LOSMAPIMOD	3	PRKACG
UCN-01	2	PRKACG
BMS-754807	2	PRKACG
ELLAGIC ACID	2	PRKACG
SONOLISIB	2	PRKACG
AT-9283	2	PRKACG
AMG-208	2	PRKACG
PF-03758309	1	PRKACG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PRKACG	268	Binding:261, Functional:6, ADMET:1
GNE	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKACG	2.7.11.11	cAMP-dependent protein kinase
GNE	2.7.1.60, 3.2.1.183, 5.1.3.14	N-acylmannosamine kinase, UDP-N-acetylglucosamine 2-epimerase (hydrolysing), UDP-N-acetylglucosamine 2-epimerase (non-hydrolysing)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PRKACG	268

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

10 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.

Compound	Max phase	Cohort target (bioactivity)
ALPELISIB	4	PRKACG
FASUDIL	3	PRKACG
LOSMAPIMOD	3	PRKACG
UCN-01	2	PRKACG
BMS-754807	2	PRKACG
ELLAGIC ACID	2	PRKACG
SONOLISIB	2	PRKACG
AT-9283	2	PRKACG
AMG-208	2	PRKACG
PF-03758309	1	PRKACG

Druggability pyramid

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

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

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)
GNE	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.