hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

Summary

hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation (MONDO:0015801) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
Mondo ID	MONDO:0015801
Orphanet	178396
ICD-11	59972355
UMLS	C5190706
MedGen	1675899
GARD	0020148
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

Related subtypes (27): factor XIII deficiency, factor VII deficiency, factor X deficiency, thrombophilia due to activated protein C resistance, hypoplasminogenemia, congenital high-molecular-weight kininogen deficiency, congenital factor XII deficiency, alpha-2-plasmin inhibitor deficiency, Tatsumi factor deficiency, East Texas bleeding disorder, inherited prekallikrein deficiency, congenital plasminogen activator inhibitor type 1 deficiency, thrombomodulin-related bleeding disorder, congenital vitamin K-dependent coagulation factors deficiency, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, congenital fibrinogen deficiency, combined deficiency of factor V and factor VIII, hemophilia, factor V deficiency, acquired coagulation factor deficiency, von Willebrand disease (hereditary or acquired), factor V short isoforms-related bleeding disorder, factor V amsterdam bleeding disorder, factor V atlanta bleeding disorder, combined deficiency of factor VII and factor X, plasminogen deficiency, type II, dysplasminogenemia

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17982	NM_001127701.1(SERPINA1):c.1145T>G (p.Met382Arg)	SERPINA1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
SERPINA1	Strong	Autosomal recessive	alpha 1-antitrypsin deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SERPINA1	Orphanet:178396	Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
SERPINA1	Orphanet:586	Cystic fibrosis
SERPINA1	Orphanet:60	Alpha-1-antitrypsin 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
SERPINA1	HGNC:8941	ENSG00000197249	P01009	Alpha-1-antitrypsin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SERPINA1	Alpha-1-antitrypsin	Inhibitor of serine proteases.

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)
SERPINA1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_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
blood	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SERPINA1	133	ubiquitous	marker	right lobe of liver, liver, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SERPINA1	3,617

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SERPINA1	P01009	46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Cargo concentration in the ER	1	335.9×	0.023	SERPINA1
COPII-mediated vesicle transport	1	163.1×	0.023	SERPINA1
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.023	SERPINA1
ER to Golgi Anterograde Transport	1	132.8×	0.023	SERPINA1
Platelet activation, signaling and aggregation	1	105.7×	0.023	SERPINA1
Transport to the Golgi and subsequent modification	1	102.9×	0.023	SERPINA1
Post-translational protein phosphorylation	1	100.2×	0.023	SERPINA1
Platelet degranulation	1	87.8×	0.023	SERPINA1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.023	SERPINA1
Asparagine N-linked glycosylation	1	60.1×	0.030	SERPINA1
Membrane Trafficking	1	37.1×	0.040	SERPINA1
Hemostasis	1	36.0×	0.040	SERPINA1
Vesicle-mediated transport	1	34.8×	0.040	SERPINA1
Innate Immune System	1	25.5×	0.050	SERPINA1
Neutrophil degranulation	1	23.1×	0.052	SERPINA1
Post-translational protein modification	1	19.2×	0.059	SERPINA1
Immune System	1	13.0×	0.081	SERPINA1
Metabolism of proteins	1	12.4×	0.081	SERPINA1

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
acute-phase response	1	421.3×	0.005	SERPINA1
blood coagulation	1	173.7×	0.006	SERPINA1

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
SERPINA1	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	SERPINA1

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)
SERPINA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.