Platelet-type bleeding disorder 18

Summary

Platelet-type bleeding disorder 18 (MONDO:0014386) is a disease caused by RASGRP2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RASGRP2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	platelet-type bleeding disorder 18
Mondo ID	MONDO:0014386
OMIM	615888
Orphanet	420566
DOID	DOID:0111051
UMLS	C4014584
MedGen	863021
GARD	0017695
Is cancer (heuristic)	no

Also known as: BDPLT18 · bleeding disorder due to calcium- and DAG-regulated guanine exchange factor-1 deficiency · bleeding disorder due to CalDAG-GEFI deficiency · bleeding disorder, platelet-type, 18 · inherited bleeding disorder, platelet-type caused by mutation in RASGRP2 · platelet-type bleeding disorder 18 · RASGRP2 inherited bleeding disorder, platelet-type

Data availability: 26 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 › platelet-type bleeding disorder 18

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 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

26 retrieved; paginated sample, class counts are floors:

11 pathogenic, 5 benign, 5 likely pathogenic, 3 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
139647	NM_001098671.2(RASGRP2):c.742G>T (p.Gly248Trp)	RASGRP2	Pathogenic	no assertion criteria provided
1677270	NM_001098671.2(RASGRP2):c.337C>T (p.Arg113Ter)	RASGRP2	Pathogenic	criteria provided, single submitter
1677271	NM_001098671.2(RASGRP2):c.1142C>T (p.Ser381Phe)	RASGRP2	Pathogenic	criteria provided, single submitter
1679094	NM_001098671.2(RASGRP2):c.706C>T (p.Gln236Ter)	RASGRP2	Pathogenic	criteria provided, single submitter
4819244	RASGRP2, SER381PHE	RASGRP2	Pathogenic	no assertion criteria provided
4819245	Q236*	RASGRP2	Pathogenic	no assertion criteria provided
4819246	R113*	RASGRP2	Pathogenic	no assertion criteria provided
4819247	G305D	RASGRP2	Pathogenic	no assertion criteria provided
4819248	C296Y	RASGRP2	Pathogenic	no assertion criteria provided
4819249	RASGRP2, IVS2, G-C, -1	RASGRP2	Pathogenic	no assertion criteria provided
627002	NM_001098671.2(RASGRP2):c.1490del (p.Phe497fs)	RASGRP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812732	NM_001098671.2(RASGRP2):c.1479dup (p.Arg494fs)	RASGRP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1677269	NM_001098671.2(RASGRP2):c.887G>A (p.Cys296Tyr)	RASGRP2	Likely pathogenic	criteria provided, single submitter
1684408	NM_001098671.2(RASGRP2):c.742G>C (p.Gly248Arg)	RASGRP2	Likely pathogenic	no assertion criteria provided
417937	NM_001098671.2(RASGRP2):c.1480dup (p.Arg494fs)	RASGRP2	Likely pathogenic	no assertion criteria provided
627184	NM_001098671.2(RASGRP2):c.914G>A (p.Gly305Asp)	RASGRP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
812733	NM_001098671.2(RASGRP2):c.1033G>C (p.Ala345Pro)	RASGRP2	Likely pathogenic	no assertion criteria provided
417938	NM_001098671.2(RASGRP2):c.542T>C (p.Phe181Ser)	RASGRP2	Conflicting classifications of pathogenicity	no assertion criteria provided
1684320	NM_001098671.2(RASGRP2):c.1717C>T (p.Arg573Cys)	RASGRP2	Uncertain significance	no assertion criteria provided
2664785	NM_001098671.2(RASGRP2):c.371+5G>T	RASGRP2	Uncertain significance	criteria provided, single submitter
4079848	NM_001098671.2(RASGRP2):c.615_616delinsCA (p.Gln205_Trp206delinsHisArg)	RASGRP2	Uncertain significance	criteria provided, single submitter
1231140	NM_001098671.2(RASGRP2):c.523-34A>G	RASGRP2	Benign	criteria provided, multiple submitters, no conflicts
1248539	NM_001098671.2(RASGRP2):c.1591+45T>G	RASGRP2	Benign	criteria provided, multiple submitters, no conflicts
1259868	NM_001098671.2(RASGRP2):c.372-45T>G	RASGRP2	Benign	criteria provided, multiple submitters, no conflicts
1287361	NM_001098671.2(RASGRP2):c.1096-44T>C	RASGRP2	Benign	criteria provided, multiple submitters, no conflicts
1289252	NM_001098671.2(RASGRP2):c.1174-43T>C	RASGRP2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
RASGRP2	Definitive	Autosomal recessive	platelet-type bleeding disorder 18	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RASGRP2	Orphanet:420566	Bleeding disorder due to CalDAG-GEFI deficiency

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
RASGRP2	HGNC:9879	ENSG00000068831	Q7LDG7	RAS guanyl-releasing protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RASGRP2	RAS guanyl-releasing protein 2	Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP.

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)
RASGRP2	Other/Unknown	no		Ras-like_Gua-exchang_fac_N, RASGEF_cat_dom, EF_hand_dom

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
granulocyte	1
monocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RASGRP2	253	broad	marker	granulocyte, spleen, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RASGRP2	1,688

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RASGRP2	Q7LDG7	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Rap1 signalling	1	713.8×	0.003	RASGRP2
Effects of PIP2 hydrolysis	1	456.8×	0.003	RASGRP2
Integrin signaling	1	423.0×	0.003	RASGRP2
FCERI mediated NF-kB activation	1	156.4×	0.006	RASGRP2

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
positive regulation of GTPase activity	1	276.3×	0.006	RASGRP2
regulation of cell growth	1	221.7×	0.006	RASGRP2
Ras protein signal transduction	1	205.5×	0.006	RASGRP2
cellular response to calcium ion	1	200.6×	0.006	RASGRP2
signal transduction	1	16.1×	0.062	RASGRP2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
RASGRP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	RASGRP2

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)
RASGRP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.