KLK12

Summary

KLK12 (kallikrein related peptidase 12, HGNC:6360) is a protein-coding gene on chromosome 19q13.41, encoding Kallikrein-12 (Q9UKR0).

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. Alternate splicing of this gene results in three transcript variants encoding different isoforms.

Source: NCBI Gene 43849 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 60 total
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency dosage sensitivity unlikely, triplosensitivity no evidence
• MANE Select transcript: NM_001370125

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6360
Approved symbol	KLK12
Name	kallikrein related peptidase 12
Location	19q13.41
Locus type	gene with protein product
Status	Approved
Aliases	KLK-L5
Ensembl gene	ENSG00000186474
Ensembl biotype	protein_coding
OMIM	605539
Entrez	43849

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 3 nonsense_mediated_decay

ENST00000250351, ENST00000319590, ENST00000525263, ENST00000526824, ENST00000529888, ENST00000530943, ENST00000531374, ENST00000684732, ENST00000967254

RefSeq mRNA: 7 — MANE Select: NM_001370125 NM_001370125, NM_001370126, NM_001370127, NM_001370128, NM_019598, NM_145894, NM_145895

CCDS: CCDS12820, CCDS12821

Canonical transcript exons

ENST00000684732 — 6 exons

Exon	Start	End
ENSE00001324317	51031876	51032135
ENSE00002267467	51034585	51034640
ENSE00003551064	51030788	51030921
ENSE00003656579	51033980	51034139
ENSE00003918064	51034806	51035002
ENSE00003921163	51029094	51029457

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 99.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4708 / max 169.2573, expressed in 60 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182365	0.2006	39
182362	0.1038	18
182366	0.0733	22
182363	0.0305	10
182364	0.0286	12
182360	0.0190	4
182361	0.0150	4

Top tissues by expression

259 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.33	gold quality
gingiva	UBERON:0001828	96.29	gold quality
gingival epithelium	UBERON:0001949	95.71	gold quality
esophagus squamous epithelium	UBERON:0006920	95.06	gold quality
esophagus mucosa	UBERON:0002469	94.62	gold quality
epithelium of esophagus	UBERON:0001976	94.61	gold quality
oral cavity	UBERON:0000167	93.60	gold quality
squamous epithelium	UBERON:0006914	93.43	gold quality
cervix epithelium	UBERON:0004801	91.33	gold quality
tongue squamous epithelium	UBERON:0006919	85.45	gold quality
tongue	UBERON:0001723	84.91	gold quality
pharyngeal mucosa	UBERON:0000355	84.00	gold quality
cervix squamous epithelium	UBERON:0006922	83.66	silver quality
body of tongue	UBERON:0011876	83.12	gold quality
superior surface of tongue	UBERON:0007371	82.38	gold quality
mouth mucosa	UBERON:0003729	81.41	gold quality
vagina	UBERON:0000996	80.68	gold quality
minor salivary gland	UBERON:0001830	79.42	gold quality
amniotic fluid	UBERON:0000173	79.02	gold quality
pancreatic ductal cell	CL:0002079	79.00	silver quality
buccal mucosa cell	CL:0002336	78.30	gold quality
periodontal ligament	UBERON:0008266	77.16	silver quality
saliva-secreting gland	UBERON:0001044	76.74	gold quality
sperm	CL:0000019	75.59	gold quality
ileal mucosa	UBERON:0000331	75.11	silver quality
tonsil	UBERON:0002372	75.07	gold quality
male germ cell	CL:0000015	74.58	gold quality
type B pancreatic cell	CL:0000169	73.68	gold quality
oviduct epithelium	UBERON:0004804	72.25	gold quality
jejunal mucosa	UBERON:0000399	72.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.83

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 40 (dosage sensitivity unlikely), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 14)

• 4 types of polymorphisms were found in Japanese gastric cancer: 1 at an intron 4 splice-donor site (c.457+2T>C), 2 in exon 6 (c.618_619delTG:p.Cys206fsX72 & c.735G>A:p.Met245Ile), & 1 in intron 3. c.457+2C/C has no hK12 serine protease expression. (PMID:15300858)
• KLK12 has trypsin-like activity, cleaving peptide bonds after both arginine & lysine. It quickly loses its activity due to autodegradation, its activity can also be rapidly inhibited by zinc ions & by alpha2-antiplasmin through covalent complex formation. (PMID:17391064)
• Serine protease of Kazal-type (SPINK6) expressed in normal human skin is a potent natural inhibitor of Kallikrein-related peptidases, KLK12 and KLK13. (PMID:21439340)
• KLK12 may indirectly regulate the bioavailability and activity of several growth factors through processing of their CCN binding partners (PMID:21628462)
• Data indicate that the KLK12 SNP rs3865443 was not associated with tumor aggressiveness but showed marginal association with prostate cancer risk for the rare homozygote. (PMID:21741862)
• Results suggest that kallikrein-related peptidase 12 (KLK12) splice variant KLK12sv3 can be regarded as a marker of good prognosis in breast cancer. (PMID:22351561)
• the proangiogenic activity of KLK12 in lung endothelial cells was not related to a kinin release (PMID:23152405)
• KLK12 gene is markedly overexpressed in gastric cancer (PMID:23236234)
• Kallikrein 5 and kallikrein 12 cleave human influenza hemagglutinins and activate thrombolytic zymogens. (PMID:23612974)
• KLK12 gene silencing reduces gastric cancer cell proliferation and migration. (PMID:27706634)
• results demonstrate the discriminative value of KLK12sv1/2 and KLK12sv3 between benign and malignant breast tumors as well as their potential favorable prognostic significance in breast adenocarcinoma. (PMID:29807016)
• novel KLK11 and KLK12 splice variants represent new potential cancer biomarkers (PMID:29874189)
• KLK12 was overexpressed in colorectal cancer. (PMID:31485623)
• Prognostic value of kallikrein-related peptidase 12 (KLK12) mRNA expression in triple-negative breast cancer patients. (PMID:32028882)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klk12	ENSMUSG00000044430
rattus_norvegicus	Klk12	ENSRNOG00000034012
drosophila_melanogaster	CG9673	FBGN0030775
drosophila_melanogaster	CG4477	FBGN0035971
drosophila_melanogaster	CG17404	FBGN0038001
drosophila_melanogaster	CG12256	FBGN0038002
drosophila_melanogaster	CG3916	FBGN0038003
drosophila_melanogaster	CG17477	FBGN0038479
drosophila_melanogaster	CG4053	FBGN0038482
drosophila_melanogaster	CG31269	FBGN0051269
drosophila_melanogaster	CG32808	FBGN0052808
drosophila_melanogaster	Phae2	FBGN0263235
drosophila_melanogaster	Send2	FBGN0264253

Paralogs (12): PRSS54 (ENSG00000103023), KLK14 (ENSG00000129437), KLK8 (ENSG00000129455), TMPRSS4 (ENSG00000137648), KLK3 (ENSG00000142515), KLK1 (ENSG00000167748), KLK4 (ENSG00000167749), KLK2 (ENSG00000167751), KLK5 (ENSG00000167754), KLK11 (ENSG00000167757), KLK7 (ENSG00000169035), PRSS58 (ENSG00000258223)

Protein

Protein identifiers

Kallikrein-12 — Q9UKR0 (reviewed: Q9UKR0)

Alternative names: Kallikrein-like protein 5

All UniProt accessions (4): Q9UKR0, A0A024R4M4, E9PPC6, E9PR22

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Similarity. Belongs to the peptidase S1 family. Kallikrein subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UKR0-1	1	yes
Q9UKR0-2	2
Q9UKR0-3	3

RefSeq proteins (7): NP_001357054, NP_001357055, NP_001357056, NP_001357057, NP_062544, NP_665901, NP_665902 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR043504

Pfam: PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.B43 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (17 total): disulfide bond 6, splice variant 3, active site 3, glycosylation site 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKR0-F1	89.11	0.75

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 62 (charge relay system); 108 (charge relay system); 200 (charge relay system)

Disulfide bonds (6): 133–235, 140–206, 172–186, 196–222, 28–161, 47–63

Glycosylation sites (2): 24, 163

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization

MSigDB gene sets: 59 (showing top): GOCC_SECRETORY_GRANULE, SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, GGGTGGRR_PAX4_03, GOBP_PROTEIN_MATURATION, TGANTCA_AP1_C, DURCHDEWALD_SKIN_CARCINOGENESIS_DN, GOCC_SECRETORY_VESICLE, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, DODD_NASOPHARYNGEAL_CARCINOMA_DN, AP1_Q6_01, MARTENS_TRETINOIN_RESPONSE_UP, WAGSCHAL_EHMT2_TARGETS_UP, CACBINDINGPROTEIN_Q6, REACTOME_KERATINIZATION

GO Biological Process (2): proteolysis (GO:0006508), protein maturation (GO:0051604)

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), secretory granule (GO:0030141)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
gene expression	1
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1
endomembrane system	1
secretory vesicle	1

Protein interactions and networks

STRING

754 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLK12	SPINK6	Q6UWN8	491
KLK12	KLK14	Q9P0G3	433
KLK12	SPINK5	Q9NQ38	410
KLK12	CRCT1	Q9UGL9	368
KLK12	SEMG2	Q02383	353
KLK12	SPINK7	P58062	351
KLK12	ZFYVE9	O95405	336
KLK12	GLOD5	A6NK44	334
KLK12	ZNF784	Q8NCA9	328
KLK12	KRT4	P19013	304
KLK12	OR52N4	Q8NGI2	302
KLK12	SPRR2G	Q9BYE4	297
KLK12	SCGB1D2	O95969	277
KLK12	ZNF681	Q96N22	277
KLK12	KRT80	Q6KB66	272

IntAct

2 interactions, top by confidence:

A	B	Type	Score
KLK12	NEMF	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): NEMF (Affinity Capture-MS), UTP11L (Affinity Capture-MS), TUBA8 (Affinity Capture-MS), TRO (Affinity Capture-MS), RABL6 (Affinity Capture-MS), MAP1A (Affinity Capture-MS), FOCAD (Affinity Capture-MS), ATP7A (Affinity Capture-MS), RBMXL1 (Affinity Capture-MS)

ESM2 similar proteins: A6NIE9, O35164, O43240, P00746, P00770, P03953, P05981, P06870, P07288, P09582, P12323, P15944, P20151, P20160, P20231, P21845, P22457, P32038, P35034, P49862, P50343, P51124, P51779, P69526, P80015, Q00356, Q03238, Q05511, Q07276, Q14B24, Q15661, Q28773, Q3T0A3, Q3UP87, Q571E5, Q5R5E8, Q6GPI1, Q6IE59, Q7JIG6, Q80WM7

Diamond homologs: A8JUP7, B1AC87, B1AC88, B1AC89, B1AC90, C0HKF7, C0HKF8, C6ZDB5, D3ZTE0, G5AE35, O60235, O97366, O97370, O97399, O97507, P00766, P00768, P00769, P04813, P07338, P11034, P12788, P15944, P15949, P16294, P16296, P17538, P19236, P20231, P20918, P21845, P24664, P26262, P29786, P29787, P35005, P35033, P35035, P35036, P35038

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

60 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

669 predictions. Top by Δscore:

Variant	Effect	Δscore
19:51030922:C:CC	acceptor_gain	1.0000
19:51031874:A:AC	donor_gain	1.0000
19:51031874:ACT:A	donor_gain	1.0000
19:51031875:C:CC	donor_gain	1.0000
19:51031875:CT:C	donor_gain	1.0000
19:51031875:CTC:C	donor_gain	1.0000
19:51029453:TCACC:T	acceptor_gain	0.9900
19:51029454:CACC:C	acceptor_gain	0.9900
19:51029454:CACCC:C	acceptor_gain	0.9900
19:51029456:CC:C	acceptor_gain	0.9900
19:51029457:CC:C	acceptor_gain	0.9900
19:51029458:C:CC	acceptor_gain	0.9900
19:51029458:CT:C	acceptor_loss	0.9900
19:51029459:T:A	acceptor_loss	0.9900
19:51030786:A:AG	donor_loss	0.9900
19:51030787:CC:C	donor_loss	0.9900
19:51030917:TGGGT:T	acceptor_gain	0.9900
19:51030918:GGGT:G	acceptor_gain	0.9900
19:51030920:GT:G	acceptor_gain	0.9900
19:51031869:CCCTT:C	donor_loss	0.9900
19:51031870:CCTTA:C	donor_loss	0.9900
19:51031871:CTTAC:C	donor_loss	0.9900
19:51031872:TTA:T	donor_loss	0.9900
19:51031873:TACTC:T	donor_loss	0.9900
19:51031875:CTCCG:C	donor_gain	0.9900
19:51031900:AG:A	donor_gain	0.9900
19:51034800:TCTCA:T	donor_loss	0.9900
19:51034801:CTCAC:C	donor_loss	0.9900
19:51034802:TCA:T	donor_loss	0.9900
19:51034803:CA:C	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000053353 (19:51036554 C>T), RS1000646429 (19:51032808 G>A), RS1000953191 (19:51032629 C>T), RS1001308962 (19:51032089 A>G,T), RS1002149454 (19:51033177 C>G), RS1002457878 (19:51032874 C>G), RS1002895439 (19:51028740 G>A), RS1002987143 (19:51028915 C>T), RS1003030810 (19:51034287 A>G), RS1003044725 (19:51034411 G>A,C,T), RS1003722504 (19:51030428 C>G), RS1004463902 (19:51029721 C>T), RS1004626784 (19:51034967 G>A,T), RS1004897692 (19:51029350 A>G), RS1004928617 (19:51031512 C>A)

Disease associations

OMIM: gene MIM:605539 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4943 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PubChem BioAssay actives

1 with measured affinity, of 7 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
sodium [(2R)-3-[[(2S)-1-[[(2S,5S,8S,11R,12S,15Z,18S,21R)-2,5-dibenzyl-8-[(2R)-butan-2-yl]-15-ethylidene-21-hydroxy-4,11-dimethyl-3,6,9,13,16,22-hexaoxo-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-2-methoxy-3-oxopropyl] sulfate	732088: Inhibition of Kallikrein-12 (unknown origin) using VPR-AMC substrate incubated for 15 mins prior to substrate addition measured for 2 hrs	ic50	10.0000	uM

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	2
Air Pollutants	increases expression, increases abundance	1
Cisplatin	affects response to substance	1
Diethylhexyl Phthalate	decreases expression	1
Smoke	increases abundance, increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2339092	Binding	Inhibition of Kallikrein-12 (unknown origin) using VPR-AMC substrate assessed as residual activity at 10 uM incubated for 15 mins prior to substrate addition measured for 2 hrs	Potent elastase inhibitors from cyanobacteria: structural basis and mechanisms mediating cytoprotective and anti-inflammatory effects in bronchial epithelial cells. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.