KLKB1
Chr 4ARkallikrein B1
Also known as: KLK3, PKK, PKKD, PPK
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.
Primary Disease Associations & Inheritance
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
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.
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.
ClinVar Variant Classifications
179 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 1 | 61 | 0 | 62 |
Likely Pathogenic | 3 | 1 | 8 | 0 | 12 |
VUS | 1 | 59 | 22 | 0 | 82 |
Likely Benign | 0 | 5 | 2 | 3 | 10 |
Benign | 0 | 0 | 4 | 1 | 5 |
Conflicting | — | 1 | |||
| Total | 4 | 66 | 97 | 4 | 172 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
KLKB1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools