Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies

Summary

Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (MONDO:0958000) is a disease caused by RAP1B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: RAP1B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies
Mondo ID	MONDO:0958000
OMIM	620654
UMLS	C5882734
MedGen	1846947
GARD	0026906
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytopenia › inherited thrombocytopenia › thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies

Related subtypes (20): thrombocytopenia 2, thrombocytopenia, cyclic, thrombocytopenia 3, congenital thrombotic thrombocytopenic purpura, thrombocytopenia, X-linked, with or without dyserythropoietic anemia, thrombocytopenia 1, thrombocytopenia 4, thrombocytopenia 5, autosomal dominant macrothrombocytopenia, isolated delta-storage pool disease, syndromic constitutional thrombocytopenia, alpha granule disease, thrombocytopenia 7, macrothrombocytopenia, isolated, congenital autosomal recessive small-platelet thrombocytopenia, congenital amegakaryocytic thrombocytopenia, thrombocytopenia 9, thrombocytopenia 10, thrombocytopenia 12 with or without myopathy, thrombocytopenia 13, syndromic

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 likely pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2672306	NM_001010942.3(RAP1B):c.35G>T (p.Gly12Val)	RAP1B	Pathogenic	no assertion criteria provided
2672307	NM_001010942.3(RAP1B):c.178G>C (p.Gly60Arg)	RAP1B	Pathogenic	no assertion criteria provided
2672309	NM_001010942.3(RAP1B):c.35G>A (p.Gly12Glu)	RAP1B	Pathogenic	no assertion criteria provided
2674587	NM_001010942.3(RAP1B):c.178G>A (p.Gly60Arg)	RAP1B	Pathogenic	no assertion criteria provided
1300148	NM_001010942.3(RAP1B):c.176C>G (p.Ala59Gly)	RAP1B	Likely pathogenic	criteria provided, single submitter
3906924	NM_001010942.3(RAP1B):c.34G>A (p.Gly12Arg)	RAP1B	Likely pathogenic	criteria provided, single submitter
3377234	NM_001010942.3(RAP1B):c.11A>G (p.Tyr4Cys)	RAP1B	Uncertain significance	criteria provided, single submitter
4293419	NM_001010942.3(RAP1B):c.145C>G (p.Gln49Glu)	RAP1B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
RAP1B	Strong	Autosomal dominant	thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies	3

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
RAP1B	HGNC:9857	ENSG00000127314	P61224	Ras-related protein Rap-1b	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAP1B	Ras-related protein Rap-1b	GTP-binding protein that possesses intrinsic GTPase activity.

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)
RAP1B	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

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
calcaneal tendon	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAP1B	145	ubiquitous	marker	monocyte, leukocyte, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAP1B	396

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAP1B	P61224	23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
MET activates RAP1 and RAC1	1	1038.2×	0.005	RAP1B
p130Cas linkage to MAPK signaling for integrins	1	761.3×	0.005	RAP1B
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	713.8×	0.005	RAP1B
Rap1 signalling	1	713.8×	0.005	RAP1B
Integrin signaling	1	423.0×	0.005	RAP1B
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.005	RAP1B
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	300.5×	0.005	RAP1B
MAP2K and MAPK activation	1	285.5×	0.005	RAP1B
Signaling by RAF1 mutants	1	278.5×	0.005	RAP1B
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.005	RAP1B
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.005	RAP1B
Signaling downstream of RAS mutants	1	253.8×	0.005	RAP1B
Signaling by BRAF and RAF1 fusions	1	170.4×	0.006	RAP1B
Neutrophil degranulation	1	23.1×	0.043	RAP1B

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
negative regulation of synaptic vesicle exocytosis	1	3370.4×	0.001	RAP1B
regulation of cell junction assembly	1	2407.4×	0.001	RAP1B
positive regulation of integrin activation	1	1872.4×	0.001	RAP1B
negative regulation of calcium ion-dependent exocytosis	1	1872.4×	0.001	RAP1B
modification of postsynaptic structure	1	1872.4×	0.001	RAP1B
Rap protein signal transduction	1	1685.2×	0.001	RAP1B
calcium-ion regulated exocytosis	1	991.3×	0.002	RAP1B
regulation of establishment of cell polarity	1	936.2×	0.002	RAP1B
establishment of endothelial barrier	1	766.0×	0.002	RAP1B
cellular response to cAMP	1	290.6×	0.004	RAP1B
establishment of localization in cell	1	160.5×	0.007	RAP1B
cell population proliferation	1	102.8×	0.011	RAP1B
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.012	RAP1B

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
RAP1B	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	RAP1B

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)
RAP1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.