cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder

Summary

cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder (MONDO:0018794) is a disease caused by PLA2G4A (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLA2G4A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 8

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	cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder
Mondo ID	MONDO:0018794
OMIM	618372
Orphanet	477787
UMLS	C5567651
MedGen	1799074
GARD	0017857
Is cancer (heuristic)	no

Also known as: cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder · GURDP · PLA2G4A-related platelet dysfunction · platelet dysfunction due to cytosolic phospholipase-A2 alpha deficiency

Data availability: 8 ClinVar variants · 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 › cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder

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 19, platelet-type bleeding disorder 20, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, 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

8 retrieved; paginated sample, class counts are floors:

4 pathogenic, 2 benign/likely benign, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
624621	NM_024420.3(PLA2G4A):c.1723G>C (p.Asp575His)	PLA2G4A	Pathogenic	no assertion criteria provided
624622	NM_024420.3(PLA2G4A):c.2118+4_2118+7del	PLA2G4A	Pathogenic	no assertion criteria provided
9079	NM_024420.3(PLA2G4A):c.331T>C (p.Ser111Pro)	PLA2G4A	Pathogenic	no assertion criteria provided
9080	NM_024420.3(PLA2G4A):c.1454G>A (p.Arg485His)	PLA2G4A	Pathogenic	no assertion criteria provided
3362555	NM_024420.3(PLA2G4A):c.607del (p.Val203fs)	PLA2G4A	Likely pathogenic	criteria provided, single submitter
807464	NM_024420.3(PLA2G4A):c.494dup (p.Arg166fs)	PLA2G4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
765134	NM_024420.3(PLA2G4A):c.1962T>G (p.Gly654=)	PLA2G4A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1720	NM_152709.5(STOX1):c.1824A>C (p.Glu608Asp)	STOX1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
PLA2G4A	Strong	Autosomal recessive	cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLA2G4A	Orphanet:468635	Cryptogenic multifocal ulcerous stenosing enteritis
PLA2G4A	Orphanet:477787	Cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder
STOX1	Orphanet:275555	Preeclampsia

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
PLA2G4A	HGNC:9035	ENSG00000116711	P47712	Cytosolic phospholipase A2	gencc,clinvar
STOX1	HGNC:23508	ENSG00000165730	Q6ZVD7	Storkhead-box protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLA2G4A	Cytosolic phospholipase A2	Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response.
STOX1	Storkhead-box protein 1	Involved in regulating the levels of reactive oxidative species and reactive nitrogen species and in mitochondrial homeostasis in the placenta.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLA2G4A	Enzyme (other)	yes	3.1.1.4	C2_dom, LysoPLipase_cat_dom, Acyl_Trfase/lysoPLipase
STOX1	Other/Unknown	no		Storkhead-box_WHD, STOX1/2

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
cartilage tissue	1
right uterine tube	1
seminal vesicle	1
bronchial epithelial cell	1
bronchus	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLA2G4A	248	ubiquitous	marker	seminal vesicle, cartilage tissue, right uterine tube
STOX1	195	broad	marker	bronchial epithelial cell, bronchus, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLA2G4A	2,535
STOX1	820

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLA2G4A	P47712	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STOX1	Q6ZVD7	48.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
phospho-PLA2 pathway	1	5710.0×	0.002	PLA2G4A
Acyl chain remodeling of CL	1	1903.3×	0.003	PLA2G4A
Hydrolysis of LPC	1	1268.9×	0.003	PLA2G4A
Acyl chain remodelling of PI	1	671.8×	0.003	PLA2G4A
Platelet sensitization by LDL	1	671.8×	0.003	PLA2G4A
Acyl chain remodelling of PG	1	634.4×	0.003	PLA2G4A
Arachidonate metabolism	1	571.0×	0.003	PLA2G4A
Acyl chain remodelling of PS	1	519.1×	0.003	PLA2G4A
ADP signalling through P2Y purinoceptor 1	1	456.8×	0.003	PLA2G4A
Acyl chain remodelling of PC	1	423.0×	0.003	PLA2G4A
Acyl chain remodelling of PE	1	393.8×	0.003	PLA2G4A
Synthesis of PA	1	292.8×	0.004	PLA2G4A
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.005	PLA2G4A

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
positive regulation of cyclin-dependent protein kinase activity	1	8426.0×	0.002	STOX1
positive regulation of otic vesicle morphogenesis	1	8426.0×	0.002	STOX1
phosphatidylglycerol catabolic process	1	4213.0×	0.002	PLA2G4A
regulation of mitochondrial DNA metabolic process	1	4213.0×	0.002	STOX1
regulation of response to oxidative stress	1	4213.0×	0.002	STOX1
cellular response to nitrosative stress	1	2808.7×	0.002	STOX1
platelet activating factor biosynthetic process	1	2106.5×	0.003	PLA2G4A
cellular response to antibiotic	1	1203.7×	0.003	PLA2G4A
icosanoid metabolic process	1	936.2×	0.003	PLA2G4A
positive regulation of peptidyl-threonine phosphorylation	1	936.2×	0.003	STOX1
positive regulation of prostaglandin secretion	1	936.2×	0.003	PLA2G4A
positive regulation of T-helper 1 type immune response	1	842.6×	0.003	PLA2G4A
monoacylglycerol biosynthetic process	1	766.0×	0.003	PLA2G4A
positive regulation of platelet activation	1	648.1×	0.003	PLA2G4A
leukotriene biosynthetic process	1	648.1×	0.003	PLA2G4A
phosphatidylcholine catabolic process	1	648.1×	0.003	PLA2G4A
prostaglandin biosynthetic process	1	561.7×	0.003	PLA2G4A
glycerol metabolic process	1	561.7×	0.003	PLA2G4A
phosphatidylcholine acyl-chain remodeling	1	561.7×	0.003	PLA2G4A
glycerophospholipid catabolic process	1	526.6×	0.004	PLA2G4A
regulation of mitochondrion organization	1	421.3×	0.004	STOX1
positive regulation of macrophage activation	1	421.3×	0.004	PLA2G4A
positive regulation of peptidyl-serine phosphorylation	1	383.0×	0.004	STOX1
arachidonate secretion	1	351.1×	0.004	PLA2G4A
positive regulation of G2/M transition of mitotic cell cycle	1	300.9×	0.005	STOX1
regulation of mitochondrial membrane potential	1	271.8×	0.005	STOX1
arachidonate metabolic process	1	240.7×	0.006	PLA2G4A
positive regulation of G1/S transition of mitotic cell cycle	1	200.6×	0.007	STOX1
inner ear development	1	187.2×	0.007	STOX1
establishment of localization in cell	1	80.2×	0.015	PLA2G4A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PLA2G4A	ZAFIRLUKAST

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLA2G4A	3	4
STOX1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ZAFIRLUKAST	4	PLA2G4A
ECOPLADIB	2	PLA2G4A
EFIPLADIB	2	PLA2G4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PLA2G4A	95	Binding:91, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLA2G4A	3.1.1.4	phospholipase A2

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

3 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)
ZAFIRLUKAST	4	PLA2G4A
ECOPLADIB	2	PLA2G4A
EFIPLADIB	2	PLA2G4A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PLA2G4A
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	STOX1

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)
STOX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.