Glanzmann thrombasthenia 2

Summary

Glanzmann thrombasthenia 2 (MONDO:0031009) is a disease caused by ITGB3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ITGB3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 66

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Glanzmann thrombasthenia 2
Mondo ID	MONDO:0031009
OMIM	619267
UMLS	C5543273
MedGen	1782592
GARD	0016439
Is cancer (heuristic)	no

Also known as: bleeding disorder, platelet-type, 23 · Glanzmann thrombasthenia 2 · GT2

Data availability: 66 ClinVar variants · 2 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 › Glanzmann thrombasthenia › Glanzmann thrombasthenia 2

Related subtypes (1): Glanzmann thrombasthenia 1

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

66 retrieved; paginated sample, class counts are floors:

29 pathogenic, 17 uncertain significance, 16 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13564	NM_000212.3(ITGB3):c.2248C>T (p.Arg750Ter)	EFCAB13-DT	Pathogenic	reviewed by expert panel
1210194	NM_000212.3(ITGB3):c.1801T>C (p.Cys601Arg)	ITGB3	Pathogenic	reviewed by expert panel
1330338	NM_000212.3(ITGB3):c.1402G>T (p.Glu468Ter)	ITGB3	Pathogenic	reviewed by expert panel
1330349	NM_000212.3(ITGB3):c.921C>A (p.Tyr307Ter)	ITGB3	Pathogenic	reviewed by expert panel
13553	NM_000212.3(ITGB3):c.719G>A (p.Arg240Gln)	ITGB3	Pathogenic	reviewed by expert panel
13554	NM_000212.3(ITGB3):c.433G>T (p.Asp145Tyr)	ITGB3	Pathogenic	reviewed by expert panel
13560	NM_000212.3(ITGB3):c.165+1G>T	ITGB3	Pathogenic	no assertion criteria provided
13562	NM_000212.3(ITGB3):c.1199G>A (p.Cys400Tyr)	ITGB3	Pathogenic	reviewed by expert panel
13563	NG_008332.2:g.48605_58661del	ITGB3	Pathogenic	no assertion criteria provided
13565	NM_000212.3(ITGB3):c.1924G>T (p.Glu642Ter)	ITGB3	Pathogenic	reviewed by expert panel
13567	NM_000212.3(ITGB3):c.428T>G (p.Leu143Trp)	ITGB3	Pathogenic	reviewed by expert panel
1691479	NM_000212.3(ITGB3):c.2031_2041del (p.Asp677fs)	ITGB3	Pathogenic	reviewed by expert panel
1691482	NM_000212.3(ITGB3):c.422A>G (p.Tyr141Cys)	ITGB3	Pathogenic	reviewed by expert panel
1879043	NM_000212.3(ITGB3):c.725G>A (p.Arg242Gln)	ITGB3	Pathogenic	reviewed by expert panel
2428170	NM_000212.3(ITGB3):c.92_93del (p.Cys31fs)	ITGB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444336	NM_000212.3(ITGB3):c.615-1G>A	ITGB3	Pathogenic	criteria provided, single submitter
2506153	NM_000212.3(ITGB3):c.1723T>C (p.Cys575Arg)	ITGB3	Pathogenic	criteria provided, multiple submitters, no conflicts
3338985	NM_000212.3(ITGB3):c.1801T>A (p.Cys601Ser)	ITGB3	Pathogenic	criteria provided, single submitter
4689500	NM_000212.3(ITGB3):c.1591C>T (p.Gln531Ter)	ITGB3	Pathogenic	criteria provided, single submitter
812736	NM_000212.3(ITGB3):c.565C>T (p.Pro189Ser)	ITGB3	Pathogenic	reviewed by expert panel
953028	NM_000212.3(ITGB3):c.31T>C (p.Trp11Arg)	ITGB3	Pathogenic	reviewed by expert panel
953050	NM_000212.3(ITGB3):c.79+1G>A	ITGB3	Pathogenic	reviewed by expert panel
953051	NM_000212.3(ITGB3):c.2113del (p.Leu705fs)	ITGB3	Pathogenic	reviewed by expert panel
953061	NM_000212.3(ITGB3):c.505C>T (p.Arg169Ter)	ITGB3	Pathogenic	reviewed by expert panel
977131	NM_000212.3(ITGB3):c.1641C>A (p.Cys547Ter)	ITGB3	Pathogenic	reviewed by expert panel
996163	NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro)	ITGB3	Pathogenic	reviewed by expert panel
996178	NM_000212.3(ITGB3):c.709_710del (p.Ser237fs)	ITGB3	Pathogenic	reviewed by expert panel
996188	NM_000212.3(ITGB3):c.431T>G (p.Met144Arg)	ITGB3	Pathogenic	reviewed by expert panel
996193	NM_000212.3(ITGB3):c.100C>T (p.Arg34Ter)	ITGB3	Pathogenic	reviewed by expert panel
850886	NM_000212.3(ITGB3):c.777+1G>A	LOC130061044	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
ITGB3	Definitive	Autosomal recessive	Glanzmann thrombasthenia 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ITGB3	Orphanet:140957	Autosomal dominant macrothrombocytopenia
ITGB3	Orphanet:849	Glanzmann thrombasthenia
ITGB3	Orphanet:853	Fetal and neonatal alloimmune thrombocytopenia
SEC63	Orphanet:2924	Isolated polycystic liver disease

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ITGB3	HGNC:6156	ENSG00000259207	P05106	Integrin beta-3	gencc,clinvar
SEC63	HGNC:21082	ENSG00000025796	Q9UGP8	Translocation protein SEC63 homolog	clinvar
EFCAB13-DT	HGNC:55338	ENSG00000263293		EFCAB13 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITGB3	Integrin beta-3	Integrin alpha-V/beta-3 (ITGAV:ITGB3) is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor.
SEC63	Translocation protein SEC63 homolog	Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ITGB3	Other/Unknown	no		Integrin_bsu_VWA, Integrin_bsu_tail, EGF_extracell
SEC63	Other/Unknown	no		DnaJ_domain, Sec63-dom, Ig_E-set
EFCAB13-DT	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
body of pancreas	1
colonic epithelium	1
parotid gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ITGB3	199	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
SEC63	295	ubiquitous	marker	colonic epithelium, body of pancreas, parotid gland
EFCAB13-DT	155	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SEC63	3,355
ITGB3	3,274
EFCAB13-DT	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITGB3	P05106	123

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEC63	Q9UGP8	77.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 3 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
PECAM1 interactions	1	878.5×	0.009	ITGB3
Fibrin formation	1	878.5×	0.009	ITGB3
p130Cas linkage to MAPK signaling for integrins	1	761.3×	0.009	ITGB3
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	713.8×	0.009	ITGB3
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.009	ITGB3
Signal transduction by L1	1	519.1×	0.009	ITGB3
Platelet Aggregation (Plug Formation)	1	439.2×	0.009	ITGB3
Syndecan interactions	1	423.0×	0.009	ITGB3
Integrin signaling	1	423.0×	0.009	ITGB3
Signaling by RAS mutants	1	423.0×	0.009	ITGB3
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.009	ITGB3
Elastic fibre formation	1	335.9×	0.009	ITGB3
TGF-beta receptor signaling activates SMADs	1	326.3×	0.009	ITGB3
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.009	ITGB3
Molecules associated with elastic fibres	1	308.6×	0.009	ITGB3
Response of endothelial cells to shear stress	1	300.5×	0.009	ITGB3
MAP2K and MAPK activation	1	285.5×	0.009	ITGB3
Signaling by RAF1 mutants	1	278.5×	0.009	ITGB3
Cellular responses to mechanical stimuli	1	259.6×	0.009	ITGB3
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.009	ITGB3
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.009	ITGB3
Signaling downstream of RAS mutants	1	253.8×	0.009	ITGB3
Oncogenic MAPK signaling	1	248.3×	0.009	ITGB3
Signaling by VEGF	1	219.6×	0.009	ITGB3
Signaling by TGF-beta Receptor Complex	1	200.3×	0.010	ITGB3
Signaling by BRAF and RAF1 fusions	1	170.4×	0.011	ITGB3
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.011	ITGB3
Non-integrin membrane-ECM interactions	1	154.3×	0.011	ITGB3
ECM proteoglycans	1	150.3×	0.011	ITGB3
VEGFA-VEGFR2 Pathway	1	139.3×	0.012	ITGB3

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
regulation of serotonin uptake	1	8426.0×	0.003	ITGB3
positive regulation of adenylate cyclase-inhibiting opioid receptor signaling pathway	1	8426.0×	0.003	ITGB3
negative regulation of lipoprotein metabolic process	1	4213.0×	0.003	ITGB3
nitrogen cycle metabolic process	1	4213.0×	0.003	SEC63
regulation of trophoblast cell migration	1	4213.0×	0.003	ITGB3
maintenance of postsynaptic specialization structure	1	2808.7×	0.003	ITGB3
regulation of postsynaptic neurotransmitter receptor diffusion trapping	1	2808.7×	0.003	ITGB3
negative regulation of lipid transport	1	2106.5×	0.003	ITGB3
tube development	1	2106.5×	0.003	ITGB3
apolipoprotein A-I-mediated signaling pathway	1	2106.5×	0.003	ITGB3
cell-substrate junction assembly	1	1404.3×	0.004	ITGB3
positive regulation of glomerular mesangial cell proliferation	1	1404.3×	0.004	ITGB3
SRP-dependent cotranslational protein targeting to membrane	1	1053.2×	0.004	SEC63
post-translational protein targeting to membrane, translocation	1	1053.2×	0.004	SEC63
smooth muscle cell migration	1	936.2×	0.004	ITGB3
regulation of extracellular matrix organization	1	936.2×	0.004	ITGB3
angiogenesis involved in wound healing	1	842.6×	0.004	ITGB3
blood coagulation, fibrin clot formation	1	842.6×	0.004	ITGB3
negative regulation of lipid storage	1	766.0×	0.004	ITGB3
negative regulation of low-density lipoprotein particle clearance	1	766.0×	0.004	ITGB3
regulation of bone resorption	1	766.0×	0.004	ITGB3
mesodermal cell differentiation	1	766.0×	0.004	ITGB3
post-translational protein targeting to endoplasmic reticulum membrane	1	702.2×	0.004	SEC63
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.004	ITGB3
cellular response to insulin-like growth factor stimulus	1	648.1×	0.004	ITGB3
positive regulation of osteoblast proliferation	1	601.9×	0.004	ITGB3
positive regulation of fibroblast migration	1	561.7×	0.004	ITGB3
positive regulation of vascular endothelial growth factor signaling pathway	1	561.7×	0.004	ITGB3
positive regulation of vascular endothelial growth factor receptor signaling pathway	1	526.6×	0.004	ITGB3
positive regulation of cell adhesion mediated by integrin	1	526.6×	0.004	ITGB3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
ITGB3	EPTIFIBATIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ITGB3	18	4
SEC63	0	0
EFCAB13-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EPTIFIBATIDE	4	ITGB3
PACLITAXEL	4	ITGB3
TIROFIBAN	4	ITGB3
ASPIRIN	4	ITGB3
CILENGITIDE	3	ITGB3
NAFAMOSTAT	3	ITGB3
LAMIFIBAN	2	ITGB3
ROXIFIBAN	2	ITGB3
FRADAFIBAN	2	ITGB3
LOTRAFIBAN	2	ITGB3
SIBRAFIBAN	2	ITGB3
ORBOFIBAN	2	ITGB3
XEMILOFIBAN	2	ITGB3
GANTOFIBAN	2	ITGB3
ELAROFIBAN	2	ITGB3
GLPG-0187	1	ITGB3
GSK-3008348 FREE BASE	1	ITGB3
GSK-3008348	1	ITGB3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ITGB3	771	Binding:575, Functional:183, ADMET:13
SEC63	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ITGB3	771

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

18 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)
EPTIFIBATIDE	4	ITGB3
PACLITAXEL	4	ITGB3
TIROFIBAN	4	ITGB3
ASPIRIN	4	ITGB3
CILENGITIDE	3	ITGB3
NAFAMOSTAT	3	ITGB3
LAMIFIBAN	2	ITGB3
ROXIFIBAN	2	ITGB3
FRADAFIBAN	2	ITGB3
LOTRAFIBAN	2	ITGB3
SIBRAFIBAN	2	ITGB3
ORBOFIBAN	2	ITGB3
XEMILOFIBAN	2	ITGB3
GANTOFIBAN	2	ITGB3
ELAROFIBAN	2	ITGB3
GLPG-0187	1	ITGB3
GSK-3008348 FREE BASE	1	ITGB3
GSK-3008348	1	ITGB3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ITGB3
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	SEC63, EFCAB13-DT

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)
SEC63	1	—
EFCAB13-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.