Gray platelet syndrome

Summary

Gray platelet syndrome (MONDO:0007686) is a disease caused by NBEAL2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NBEAL2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 295
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000978	Bruising susceptibility	Very frequent (80-99%)
HP:0001872	Abnormality of thrombocytes	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0000140	Abnormality of the menstrual cycle	Frequent (30-79%)
HP:0000421	Epistaxis	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0002863	Myelodysplasia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	gray platelet syndrome
Mondo ID	MONDO:0007686
MeSH	D055652
OMIM	139090
Orphanet	721
DOID	DOID:0111044
ICD-11	1818085572
NCIT	C84741
SNOMED CT	51720005
UMLS	C0272302
MedGen	82900
GARD	0002562
Is cancer (heuristic)	no

Also known as: Alpha storage pool deficiency · BDPLT4 · GPS · gray platelet syndrome · marked decrease or absence of alpha-granules and of platelet-specific alpha-granule proteins · platelet alpha-granule deficiency

Data availability: 295 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

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

Related subtypes (27): 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, 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

295 retrieved; paginated sample, class counts are floors:

164 uncertain significance, 29 likely pathogenic, 29 pathogenic, 28 benign, 28 conflicting classifications of pathogenicity, 10 benign/likely benign, 5 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1300139	NM_015175.3(NBEAL2):c.5476dup (p.Arg1826fs)	NBEAL2	Pathogenic	criteria provided, multiple submitters, no conflicts
2443319	NM_015175.3(NBEAL2):c.7460_7461del (p.Thr2487fs)	NBEAL2	Pathogenic	no assertion criteria provided
31116	NM_015175.3(NBEAL2):c.2701C>T (p.Arg901Ter)	NBEAL2	Pathogenic	no assertion criteria provided
31117	NM_015175.3(NBEAL2):c.881C>G (p.Ser294Ter)	NBEAL2	Pathogenic	no assertion criteria provided
31118	NM_015175.3(NBEAL2):c.1163T>C (p.Leu388Pro)	NBEAL2	Pathogenic	no assertion criteria provided
31119	NM_015175.3(NBEAL2):c.1928A>T (p.Glu643Val)	NBEAL2	Pathogenic	no assertion criteria provided
31120	NM_015175.3(NBEAL2):c.6299C>T (p.Pro2100Leu)	NBEAL2	Pathogenic	no assertion criteria provided
31121	NM_015175.3(NBEAL2):c.1823G>A (p.Trp608Ter)	NBEAL2	Pathogenic	criteria provided, single submitter
31122	NM_015175.3(NBEAL2):c.5413dup (p.Ala1805fs)	NBEAL2	Pathogenic	no assertion criteria provided
3606036	NM_015175.3(NBEAL2):c.4485-1G>A	NBEAL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3768691	NC_000003.11:g.(?47021155)(47021403_47030158)del	NBEAL2	Pathogenic	criteria provided, single submitter
4277723	NM_015175.3(NBEAL2):c.2953C>T (p.Arg985Ter)	NBEAL2	Pathogenic	criteria provided, single submitter
435927	NM_015175.3(NBEAL2):c.1793G>A (p.Trp598Ter)	NBEAL2	Pathogenic	criteria provided, single submitter
435928	NM_015175.3(NBEAL2):c.4081G>T (p.Glu1361Ter)	NBEAL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4530588	NM_015175.3(NBEAL2):c.3222-2A>T	NBEAL2	Pathogenic	criteria provided, single submitter
627258	NM_015175.3(NBEAL2):c.1789C>T (p.Arg597Ter)	NBEAL2	Pathogenic	criteria provided, multiple submitters, no conflicts
627345	NM_015175.3(NBEAL2):c.607dup (p.Ile203fs)	NBEAL2	Pathogenic	criteria provided, single submitter
627372	NM_015175.3(NBEAL2):c.7387C>T (p.Gln2463Ter)	NBEAL2	Pathogenic	criteria provided, single submitter
812961	NM_015175.3(NBEAL2):c.3118+2T>G	NBEAL2	Pathogenic	criteria provided, single submitter
812962	NM_015175.3(NBEAL2):c.6432del (p.Phe2144fs)	NBEAL2	Pathogenic	criteria provided, single submitter
982270	NM_015175.3(NBEAL2):c.1725_1728dup (p.Ala577fs)	NBEAL2	Pathogenic	criteria provided, single submitter
982272	NM_015175.3(NBEAL2):c.2751dup (p.Asp918Ter)	NBEAL2	Pathogenic	criteria provided, single submitter
982274	NM_015175.3(NBEAL2):c.4928_4929del (p.Asp1643fs)	NBEAL2	Pathogenic	criteria provided, single submitter
982276	NM_015175.3(NBEAL2):c.7192_7202dup (p.Gln2402fs)	NBEAL2	Pathogenic	criteria provided, single submitter
982277	NM_015175.3(NBEAL2):c.4890del (p.Arg1631fs)	NBEAL2	Pathogenic	criteria provided, single submitter
982278	NM_015175.3(NBEAL2):c.7506del (p.Asp2503fs)	NBEAL2	Pathogenic	criteria provided, single submitter
982279	NM_015175.3(NBEAL2):c.6920-1G>C	NBEAL2	Pathogenic	criteria provided, single submitter
982280	NM_015175.3(NBEAL2):c.6568del (p.Cys2190fs)	NBEAL2	Pathogenic	criteria provided, single submitter
982282	NM_015175.3(NBEAL2):c.4485-1G>T	NBEAL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982286	NM_015175.3(NBEAL2):c.2650-1G>A	NBEAL2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
NBEAL2	Definitive	Autosomal recessive	gray platelet syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NBEAL2	Orphanet:721	Gray platelet 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
NBEAL2	HGNC:31928	ENSG00000160796	Q6ZNJ1	Neurobeachin-like protein 2	gencc,clinvar
CCDC12	HGNC:28332	ENSG00000160799	Q8WUD4	Coiled-coil domain-containing protein 12	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NBEAL2	Neurobeachin-like protein 2	Probably involved in thrombopoiesis.

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)
NBEAL2	Scaffold/PPI	no		BEACH_dom, WD40_rpt, ARM-like
CCDC12	Other/Unknown	no		mRNA_splic_Cwf18-like

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
granulocyte	1
lower esophagus mucosa	1
skin of abdomen	1
leukocyte	1
monocyte	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NBEAL2	220	ubiquitous	marker	granulocyte, lower esophagus mucosa, skin of abdomen
CCDC12	255	ubiquitous	marker	sural nerve, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCDC12	1,244
NBEAL2	1,001

Intra-cohort edges

A	B	Sources
CCDC12	NBEAL2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCDC12	Q8WUD4	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NBEAL2	Q6ZNJ1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
mRNA Splicing	1	54.9×	0.083	CCDC12
Processing of Capped Intron-Containing Pre-mRNA	1	41.1×	0.083	CCDC12
mRNA Splicing - Major Pathway	1	27.3×	0.083	CCDC12
Metabolism of RNA	1	20.8×	0.083	CCDC12
Innate Immune System	1	12.8×	0.099	NBEAL2
Neutrophil degranulation	1	11.5×	0.099	NBEAL2
Immune System	1	6.5×	0.148	NBEAL2

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
platelet formation	1	702.2×	0.003	NBEAL2
intracellular protein localization	1	104.7×	0.010	NBEAL2

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
NBEAL2	0	0
CCDC12	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	NBEAL2, CCDC12

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)
NBEAL2	0	—
CCDC12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.