KLK1

protein-coding

kallikrein 1, the group of Kallikreins

Gene summary

Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. This protein is functionally conserved in its capacity to release the vasoactive peptide, Lys-bradykinin, from low molecular weight kininogen. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002257.4

Inheritance

ClinVar variants

U:34B:5

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr19:50,819,146-50,823,787

External References & Databases

Ensembl (ENSG00000167748)

Transcript & Mutation Effects

hg38 • Region Span ~4.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pulmonary arterial hypertensionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

*KLK1* was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2019 (Zhu et al., PMID: 31727138). Seven missense, one frameshift, one stop-gain, and one splice variant were identified in a case-control study. Ten probands were identified by exome sequencing of a large cohort from the National Biological Sample and Data Repository for PAH (n = 2572 cases). One variant was recurrent in two unrelated but affected individuals. The mechanism of pathogenicity was suggested to be loss of function. The *KLK1*-PAH relationship was supported by expression in adult lung (PMID: 17573418). In summary, the evidence for a gene-disease relationship between *KLK1* and autosomal dominant PAH is limited. This classification was approved by the ClinGen Pulmonary Hypertension GCEP on 8/30/2022 (SOP Version 9). The KLK1 gene-disease relationship was re-evaluated on 1/14/2026 by the ClinGen PH Gene Curation Expert Panel (SOP v11). No new genetic evidence was identified. The previously identified *KLK1* variants (Zhu et al., PMID: 31727138) were reevaluated according to updated PH GCEP thresholds for variant inclusion: AF <= 0.0001 in gnomAD 2.1.1 control subpopulations or absent from gnomAD 4.1 subpopulations AND loss of function variant OR missense variant meeting pathogenicity score thresholds for 2 out of 3 predictors (CADD>=25.3, REVEL>=0.644, AlphaMissense >=0.792 (missense variants). Two *KLK1* missense variants did not reach the thresholds for allele frequency or pathogenicity. No new experimental evidence was identified but PAH relevant expression was confirmed in lung cells using single cell RNA-seq data (PMID: 33915568). In summary, the evidence for a gene-disease relationship between *KLK1* and autosomal dominant PAH remains classified as limited. This classification was approved by the ClinGen Pulmonary Hypertension GCEP on 1/14/2026 (SOP Version 11).

pulmonary arterial hypertensionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLK1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 37

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002257.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				1 clinvar	1 clinvar	2
missense			34 clinvar	3 clinvar		37
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	34	4	1	39

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002257.4	RefSeq	NP_002248.1	5	MANE Select
ENST00000301420.3	Ensembl	ENSP00000301420.1	5	MANE Select
ENST00000593325.5	Ensembl	ENSP00000472939.1	3	Standard
ENST00000878924.1	Ensembl	ENSP00000548983.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Renin-angiotensin system - Homo sapiens (human)
Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human)
Blood Clotting Cascade
Dengue-2 Interactions with Blood Clotting Cascade
Metabolism of proteins

Biological Process

regulation of systemic arterial blood pressure
zymogen activation

Molecular Function

serine-type endopeptidase activity

Cellular Component

nucleus
secretory granule
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301420
Coding exons: 5
Length: 4640
Individuals with no LoFs: 125705
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 125746
p: 0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.443	138	153	0.899	0.00000793	1718
Missense (PolyPhen)		44	51.223	0.85899		617
Synonymous	-1.19	77	64.8	1.19	0.00000368	514
Loss of Function	0.865	7	9.94	0.704	4.26e-7	104

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.000065	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.;

Recessive Scores

pRec: 0.420

Intolerance Scores

LoFtool: 0.401
RVIS EVS: 0.68
RVIS percentile EVS: 85.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.351

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium