Inherited prekallikrein deficiency

Summary

Inherited prekallikrein deficiency (MONDO:0012901) is a disease caused by KLKB1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KLKB1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	inherited prekallikrein deficiency
Mondo ID	MONDO:0012901
MeSH	C562725
OMIM	612423
Orphanet	749
GARD	0004477
Is cancer (heuristic)	no

Also known as: congenital prekallikrein deficiency · fletcher factor (prekallikrein) deficiency · hereditary prekallikrein deficiency · prekallikrein deficiency, congenital

Data availability: 18 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › inherited prekallikrein deficiency

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, congenital plasminogen activator inhibitor type 1 deficiency, thrombomodulin-related bleeding disorder, congenital vitamin K-dependent coagulation factors deficiency, hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation, 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

18 retrieved; paginated sample, class counts are floors:

5 likely pathogenic, 3 benign/likely benign, 3 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 2 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1803725	NM_000892.5(KLKB1):c.1204_1205del (p.Trp402fs)	KLKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803727	NM_000892.5(KLKB1):c.143_221+128del	KLKB1	Pathogenic	criteria provided, single submitter
1803774	NM_000892.5(KLKB1):c.1196G>A (p.Trp399Ter)	KLKB1	Pathogenic	criteria provided, single submitter
225400	NM_000892.5(KLKB1):c.1259G>A (p.Gly420Glu)	KLKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1801471	NM_000892.5(KLKB1):c.689T>A (p.Ile230Asn)	KLKB1	Likely pathogenic	criteria provided, single submitter
3065306	NM_000892.5(KLKB1):c.870del (p.Glu290fs)	KLKB1	Likely pathogenic	criteria provided, single submitter
3068022	NM_000892.5(KLKB1):c.940G>T (p.Gly314Ter)	KLKB1	Likely pathogenic	criteria provided, single submitter
3779797	NM_000892.5(KLKB1):c.1606C>T (p.Gln536Ter)	KLKB1	Likely pathogenic	criteria provided, single submitter
4081475	NM_000892.5(KLKB1):c.204_207del (p.Ile68fs)	KLKB1	Likely pathogenic	criteria provided, single submitter
12035	NM_000892.5(KLKB1):c.1643G>A (p.Cys548Tyr)	KLKB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
711923	NM_000892.5(KLKB1):c.451dup (p.Ser151fs)	KLKB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1696442	NM_000892.5(KLKB1):c.-2+1G>C	KLKB1	Uncertain significance	criteria provided, single submitter
3590463	NM_000892.5(KLKB1):c.1581G>C (p.Glu527Asp)	KLKB1	Uncertain significance	criteria provided, single submitter
3779798	NM_000892.5(KLKB1):c.759-1G>A	KLKB1	Uncertain significance	criteria provided, single submitter
12037	NM_000892.5(KLKB1):c.428G>A (p.Ser143Asn)	KLKB1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
789581	NM_000892.5(KLKB1):c.808A>G (p.Thr270Ala)	KLKB1	Benign	criteria provided, multiple submitters, no conflicts
791992	NM_000892.5(KLKB1):c.519A>G (p.Gly173=)	KLKB1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
791993	NM_000892.5(KLKB1):c.1072A>G (p.Thr358Ala)	KLKB1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
KLKB1	Strong	Autosomal recessive	inherited prekallikrein deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KLKB1	Orphanet:749	Congenital prekallikrein 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
KLKB1	HGNC:6371	ENSG00000164344	P03952	Plasma kallikrein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLKB1	Plasma kallikrein	Participates in the surface-dependent activation of blood coagulation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KLKB1	Protease	yes	3.4.21.34	Apple, Trypsin_dom, Peptidase_S1A

Expression context

Cohort genes with no expression data: 0.

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
liver	1
primordial germ cell in gonad	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLKB1	196	tissue_specific	yes	right lobe of liver, liver, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLKB1	1,537

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KLKB1	P03952	22

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
R-HSA-9651496	1	3806.7×	0.001	KLKB1
Defective factor XII causes hereditary angioedema	1	2855.0×	0.001	KLKB1
Defective SERPING1 causes hereditary angioedema	1	2855.0×	0.001	KLKB1
Diseases of hemostasis	1	2855.0×	0.001	KLKB1
R-HSA-140837	1	1427.5×	0.002	KLKB1
Regulation of FXIIa and plasma kallikrein activity	1	1142.0×	0.002	KLKB1
FXIIa, PKa-dependent activation of coagulation pathway	1	1142.0×	0.002	KLKB1
R-HSA-140877	1	951.7×	0.002	KLKB1
Activation of Matrix Metalloproteinases	1	308.6×	0.005	KLKB1
FXIIa activates plasma kallikrein-kinin system	1	173.0×	0.008	KLKB1
Degradation of the extracellular matrix	1	117.7×	0.011	KLKB1
Extracellular matrix organization	1	63.1×	0.018	KLKB1
Hemostasis	1	36.0×	0.030	KLKB1
Disease	1	13.1×	0.076	KLKB1

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
Factor XII activation	1	5617.3×	0.001	KLKB1
positive regulation of fibrinolysis	1	3370.4×	0.001	KLKB1
plasminogen activation	1	1296.3×	0.002	KLKB1
fibrinolysis	1	842.6×	0.002	KLKB1
zymogen activation	1	674.1×	0.002	KLKB1
blood coagulation	1	173.7×	0.007	KLKB1
proteolysis	1	34.2×	0.029	KLKB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
KLKB1	BEROTRALSTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KLKB1	10	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEROTRALSTAT	4	KLKB1
DAREXABAN	3	KLKB1
MILVEXIAN	3	KLKB1
AVORALSTAT	3	KLKB1
SEBETRALSTAT	3	KLKB1
GABEXATE	3	KLKB1
LETAXABAN	2	KLKB1
GW813893	2	KLKB1
FENIRALSTAT	2	KLKB1
BMS-962212	1	KLKB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KLKB1	300	Binding:283, ADMET:17

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KLKB1	3.4.21.34	plasma kallikrein

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KLKB1	300

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

10 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)
BEROTRALSTAT	4	KLKB1
DAREXABAN	3	KLKB1
MILVEXIAN	3	KLKB1
AVORALSTAT	3	KLKB1
SEBETRALSTAT	3	KLKB1
GABEXATE	3	KLKB1
LETAXABAN	2	KLKB1
GW813893	2	KLKB1
FENIRALSTAT	2	KLKB1
BMS-962212	1	KLKB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KLKB1
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.