KLKB1

Chr 4AR

kallikrein B1

Also known as: KLK3, PKK, PKKD, PPK

NCBI Gene: 3818 ENSG00000164344 OMIM: 229000

The protein encoded by this gene is a serine protease that participates in surface-dependent activation of blood coagulation, activates coagulation factor XII, and releases bradykinin from high molecular weight kininogen. Mutations cause Fletcher factor (prekallikrein) deficiency with autosomal recessive inheritance. The gene shows very low constraint to loss-of-function variants (pLI near zero), consistent with the recessive inheritance pattern of the associated bleeding disorder.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a glycoprotein that participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflammation. The encoded preproprotein present in plasma as a non-covalent complex with high molecular weight kininogen undergoes proteolytic processing mediated by activated coagulation factor XII to generate a disulfide-linked, heterodimeric serine protease comprised of heavy and light chains. Certain mutations in this gene cause prekallikrein deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.001 OMIM phenotype

Clinical Summary— KLKB1

🧬

Gene-Disease Validity (ClinGen)

inherited prekallikrein deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.00LOEUF

pLI 0.000

Z-score 1.54

OE 0.71 (0.52–1.00)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.70Z-score

OE missense 0.89 (0.81–0.98)

302 obs / 338.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.71 (0.52–1.00)

0≤0.351.4

Missense OE?0.89 (0.81–0.98)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 24 / 33.6Missense obs/exp: 302 / 338.2Syn Z: -1.62

This gene — mechanism propensity

0.7036th %ile

GOF

0.6345th %ile

LOF

0.3066th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.