KLK8

Summary

KLK8 (kallikrein related peptidase 8, HGNC:6369) is a protein-coding gene on chromosome 19q13.41, encoding Kallikrein-8 (O60259). Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV.

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 tandem in a gene cluster on chromosome 19. The encoded protein may be involved in proteolytic cascade in the skin and may serve as a biomarker for ovarian cancer. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 11202 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 56 total
• Druggable target: yes
• MANE Select transcript: NM_007196

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6369
Approved symbol	KLK8
Name	kallikrein related peptidase 8
Location	19q13.41
Locus type	gene with protein product
Status	Approved
Aliases	HNP, TADG14, neuropsin, ovasin
Ensembl gene	ENSG00000129455
Ensembl biotype	protein_coding
OMIM	605644
Entrez	11202

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000291726, ENST00000320838, ENST00000347619, ENST00000391806, ENST00000593490, ENST00000594669, ENST00000594914, ENST00000595238, ENST00000598195, ENST00000599710, ENST00000600767, ENST00000695909, ENST00000867224, ENST00000867225, ENST00000867226, ENST00000913986, ENST00000913987, ENST00000913988

RefSeq mRNA: 5 — MANE Select: NM_007196 NM_001281431, NM_007196, NM_144505, NM_144506, NM_144507

CCDS: CCDS12813, CCDS12814, CCDS12815, CCDS42600, CCDS74433

Canonical transcript exons

ENST00000695909 — 6 exons

Exon	Start	End
ENSE00001376559	51000424	51000583
ENSE00003077115	51001532	51001604
ENSE00003597000	50996008	50996214
ENSE00003632093	50997751	50997884
ENSE00003679747	51001098	51001175
ENSE00003750386	50999996	51000258

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 98.42.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7805 / max 140.3933, expressed in 233 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182320	0.8362	107
182319	0.6590	137
182318	0.1206	57
182322	0.0608	29
208909	0.0560	12
182317	0.0307	10
182321	0.0172	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.42	gold quality
skin of abdomen	UBERON:0001416	96.55	gold quality
skin of leg	UBERON:0001511	96.50	gold quality
esophagus mucosa	UBERON:0002469	94.93	gold quality
zone of skin	UBERON:0000014	93.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.68	gold quality
right uterine tube	UBERON:0001302	88.84	gold quality
vagina	UBERON:0000996	79.10	gold quality
penis	UBERON:0000989	79.04	gold quality
oral cavity	UBERON:0000167	78.19	gold quality
minor salivary gland	UBERON:0001830	77.65	gold quality
mouth mucosa	UBERON:0003729	76.27	gold quality
mammalian vulva	UBERON:0000997	74.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.56	gold quality
left uterine tube	UBERON:0001303	74.48	gold quality
ectocervix	UBERON:0012249	73.46	gold quality
esophagus	UBERON:0001043	73.28	gold quality
omental fat pad	UBERON:0010414	71.57	gold quality
peritoneum	UBERON:0002358	71.53	gold quality
saliva-secreting gland	UBERON:0001044	71.29	gold quality
fallopian tube	UBERON:0003889	70.52	gold quality
adipose tissue of abdominal region	UBERON:0007808	69.92	gold quality
upper leg skin	UBERON:0004262	67.51	gold quality
skin of hip	UBERON:0001554	66.32	gold quality
tonsil	UBERON:0002372	63.91	gold quality
uterine cervix	UBERON:0000002	63.00	gold quality
jejunal mucosa	UBERON:0000399	62.86	silver quality
gingiva	UBERON:0001828	62.22	gold quality
tibial nerve	UBERON:0001323	62.01	gold quality
right hemisphere of cerebellum	UBERON:0014890	60.56	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	201.71
E-MTAB-8410	yes	21.21
E-ANND-3	yes	15.37

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT5A, STAT5B

Literature-anchored findings (GeneRIF, showing 28)

• Cervical cancer expressed high level of TADG-14. May play important role in invasion and metastasis. Appears only in abundance in tumor tissue and contains secretion signal sequence. Possible diagnostic use or as therapeutic target. (PMID:14749636)
• Expression of hK8 is increased during the development of ovarian cancer and down-regulated during ovarian cancer progression. (PMID:15138549)
• Amino-terminal sequencing of the activated enzyme demonstrated the cleavage of a 9-aa propeptide from the pro-enzyme; substrate specificiy and effect of metal ions and pH is demonstrated (PMID:16800733)
• KLK8 expression confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness. (PMID:17178872)
• analysis of how a mutation leads to the origin of a novel splice form of neuropsin (KLK8), a gene involved in learning and memory (PMID:17487847)
• kallikreins 5, 7, 8, and 10 are abundantly expressed in human OSCC and may be implicated in malignant progression (PMID:19085836)
• The processed end-point enzymes are the same for both type I and type II kallikrein 8, suggesting that the emergence of type II kallikrein 8 in the human brain likely leads to functional modifications of kallikrein 8. (PMID:19125171)
• Combination of KLK2, 3, 13, and 14 and KLK1, 2, 5, 6, 7, 8, 10, 13, and 14 showed very strong discriminatory potential for semen liquefaction and viscosity, respectively. (PMID:19558318)
• The KLK8-T4 alternative splice variant, alone or in combination, may be a new independent marker of unfavorable prognosis in lung cancer. (PMID:20360129)
• The results of this study indicate that most salivary gland tumors show high levels of expression of KLK8. (PMID:20614312)
• KLK8 as a new active serine protease in human stratum corneum and sweat (PMID:20940292)
• KLK8 and KLK14 can signal differentially via the PARs to affect tissue function (PMID:22505524)
• It dissects a schizophrenic susceptibility gene, NRG1. (PMID:24614639)
• Occurring independently of cyclophilins and of furin that mediate human papillomavirus 16 L2 exposure, KLK8-mediated cleavage of L1 likely facilitated access to L2, located in the capsid lumen, and potentially uncoating. (PMID:25926655)
• KLK8 mRNA expression is associated with aggressive tumor characteristics and it can serve as a novel independent biomarker of unfavorable prognosis for BC patients. (PMID:26099606)
• mRNA expression levels of KLK6 and KLK8 in advanced serous ovarian cancer (PMID:27483364)
• elevated KLK8 expression was correlated with the progression of colorectal cancer. (PMID:28142115)
• KLK8 levels are higher in female brain and female sex hormone increases KLK8 in neuronal/glial cells. Hippocampal KLK8 protein levels were drastically increased in women patients. (PMID:29505099)
• Telbivudine treatment resulted in increased levels of serum KLK8 protein. Furthermore, eGFR increase was associated with body height-adjusted, post-treatment KLK8 levels (PMID:29936485)
• Study findings provide a comprehensive picture of the molecular mechanisms underlying the enzyme activity of recombinant human KLK8. Enzyme kinetics with optimized substrates showed stimulation by Ca2+ and inhibition by Zn2+, which are physiological regulators. Crystal structures of KLK8 with a ligand-free active site and with the inhibitor leupeptin explain the subsite specificity and display Ca2+ bound to the 75-loop. (PMID:30013126)
• Blood KLK8 was a similarly strong discriminator for mild cognitive impairment but slightly weaker for Alzheimer’s disease (PMID:31371645)
• Extracellular acidityinduced expression of Kallikreinrelated peptidases 7 and 8 is involved in increased invasiveness of gastric cancer cells. (PMID:32323843)
• The association of serum Kallikrein-8 with cognitive function in vascular dementia. (PMID:33660811)
• KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1. (PMID:34552064)
• DNA methylation of the KLK8 gene in depression symptomatology. (PMID:34715912)
• Kallikrein 8: A key sheddase to strengthen and stabilize neural plasticity. (PMID:35820483)
• circSSPO boosts growth of esophageal squamous cell carcinoma through upregulation of micrRNA-6820-5p-mediated KLK8 and PKD1 expression. (PMID:37812360)
• Tumor-derived KLK8 predicts inferior survival and promotes an immune-suppressive tumor microenvironment in lung squamous cell carcinoma. (PMID:38273291)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klk8	ENSMUSG00000064023
rattus_norvegicus	Klk8	ENSRNOG00000018580
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), TMPRSS4 (ENSG00000137648), KLK3 (ENSG00000142515), KLK1 (ENSG00000167748), KLK4 (ENSG00000167749), KLK2 (ENSG00000167751), KLK5 (ENSG00000167754), KLK11 (ENSG00000167757), KLK7 (ENSG00000169035), KLK12 (ENSG00000186474), PRSS58 (ENSG00000258223)

Protein

Protein identifiers

Kallikrein-8 — O60259 (reviewed: O60259)

Alternative names: Neuropsin, Ovasin, Serine protease 19, Serine protease TADG-14, Tumor-associated differentially expressed gene 14 protein

All UniProt accessions (4): O60259, A0A0A0MQY9, M0R231, M0R390

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV. Also cleaves L1CAM in response to increased neural activity. Induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer-collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity. Involved in skin desquamation and keratinocyte proliferation. Plays a role in the secondary phase of pathogenesis following spinal cord injury.

Subunit / interactions. Interacts with SPINK9.

Subcellular location. Secreted. Cytoplasm.

Tissue specificity. Isoform 1 is predominantly expressed in the pancreas. Isoform 2 is expressed in adult brain and hippocampus. Isoform 1 and isoform 2 are found in fetal brain and placenta. Detected in salivary gland, uterus, thymus, breast, testis and kidney but not in spleen, liver, lung or normal ovarian tissue. Displays an 11.5-fold increase in Alzheimer disease hippocampus compared to controls and is overexpressed in some ovarian carcinomas. Expressed at low levels in normal skin while high levels are found in psoriasis vulgaris, seborrheic keratosis, lichen planus and squamous cell carcinoma skin samples. Expressed in the keratinocytes.

Activity regulation. Inhibited by a range of serine protease inhibitors including antipain, aprotinin, leupeptin, benzamidine and soybean trypsin inhibitor.

Miscellaneous. Expressed at high levels in serum, ascites fluid and tumor cytosol of advanced stage ovarian cancer patients and may serve as a marker of ovarian cancer. Produced as a result of a human-specific mutation which is not found in other primates.

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

Isoforms (4)

UniProt ID	Names	Canonical?
O60259-1	1	yes
O60259-2	2
O60259-3	3
O60259-4	4

RefSeq proteins (5): NP_001268360, NP_009127, NP_653088, NP_653089, NP_653090 (=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 3.4.21.118 — kallikrein 8 (BRENDA: 5 organisms, 100 substrates, 51 inhibitors, 28 Km, 21 kcat entries)

Substrate kinetics (BRENDA)

23 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TERT-BUTYLOXYCARBONYL-PHE-SER-ARG-4-METHYLCOUMAR	0.22–0.54	3
TERT-BUTYLOXYCARBONYL-VAL-PRO-ARG-4-METHYLCOUMAR	0.27–0.3	3
D-VAL-LEU-ARG-4-NITROANILIDE	0.23–0.28	2
BENZYLOXYCARBONYL-GLY-GLY-ARG-7-AMIDO-4-METHYLCO	0.4312	1
BENZYLOXYCARBONYL-L-VAL-L-VAL-L-ARG-7-AMIDO-4-ME	0.07	1
L-PRO-L-PHE-L-ARG-7-AMIDO-4-METHYLCOUMARIN	0.07	1
PRO-PHE-ARG-4-METHYLCOUMARYL-7-AMIDE	8.36	1
PRO-PHE-ARG-7-AMIDO-4-METHYLCOUMARIN	0.1533	1
T-BUTYLOXYCARBONYL-L-LEU-L-LYS-L-ARG-7-AMIDO-4-M	0.1	1
T-BUTYLOXYCARBONYL-L-PHE-L-SER-L-ARG-7-AMIDO-4-M	0.07	1
T-BUTYLOXYCARBONYL-L-VAL-L-LEU-L-LYS-7-AMIDO-4-M	0.1	1
T-BUTYLOXYCARBONYL-L-VAL-L-PRO-L-ARG-7-AMIDO-4-M	0.07	1
TERT-BUTYLOXYCARBONYL-ASP(BENZYLOXY)-PRO-ARG-4-M	0.32	1
TERT-BUTYLOXYCARBONYL-ASP-PRO-ARG-4-METHYLCOUMAR	0.34	1
TERT-BUTYLOXYCARBONYL-GLN-ALA-ARG-7-AMIDO-4-METH	0.1844	1

UniProt features (42 total): strand 17, disulfide bond 6, splice variant 4, helix 4, active site 3, signal peptide 1, propeptide 1, sequence variant 1, sequence conflict 1, chain 1, domain 1, turn 1, glycosylation site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5MS4	X-RAY DIFFRACTION	2.1
5MS3	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60259-F1	88.79	0.76

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): 73 (charge relay system); 120 (charge relay system); 212 (charge relay system)

Disulfide bonds (6): 145–246, 152–218, 184–198, 208–233, 39–173, 58–74

Glycosylation sites (1): 110

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: 163 (showing top): GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, GOBP_KERATINOCYTE_PROLIFERATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_NEUROGENESIS, GOBP_PROTEIN_MATURATION, GOBP_CELL_JUNCTION_ORGANIZATION, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, YAMASHITA_METHYLATED_IN_PROSTATE_CANCER, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, AFFAR_YY1_TARGETS_UP, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (9): proteolysis (GO:0006508), memory (GO:0007613), response to wounding (GO:0009611), ERBB4 signaling pathway (GO:0038130), keratinocyte proliferation (GO:0043616), neuron projection morphogenesis (GO:0048812), regulation of synapse organization (GO:0050807), synapse organization (GO:0050808), protein maturation (GO:0051604)

GO Molecular Function (5): serine-type endopeptidase activity (GO:0004252), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), secretory granule (GO:0030141), serine protease inhibitor complex (GO:0097180)

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
cellular anatomical structure	2
learning or memory	1
response to stress	1
ERBB signaling pathway	1
epithelial cell proliferation	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
regulation of synapse structure or activity	1
synapse organization	1
regulation of cellular component organization	1
cell junction organization	1
gene expression	1
endopeptidase activity	1
serine-type peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
intracellular anatomical structure	1
endomembrane system	1
secretory vesicle	1
protease inhibitor complex	1

Protein interactions and networks

STRING

1038 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLK8	SPINK9	Q5DT21	923
KLK8	CRABP2	P29373	640
KLK8	TGM5	O43548	489
KLK8	SYCP2	Q9BX26	489
KLK8	RXFP4	Q8TDU9	456
KLK8	DSG4	Q86SJ6	447
KLK8	LCN2	P30150	439
KLK8	ACP4	Q9BZG2	438
KLK8	PSCA	O43653	433
KLK8	OR4D9	Q8NGE8	419
KLK8	RFC5	P40937	418
KLK8	ENAM	Q9NRM1	418
KLK8	SPINK5	Q9NQ38	416
KLK8	DYNLRB2	Q8TF09	411
KLK8	OR1K1	Q8NGR3	409

IntAct

47 interactions, top by confidence:

A	B	Type	Score
	KLK8	psi-mi:“MI:0915”(physical association)	0.560
KLK8	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
KLK8	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
KLK8	KRT34	psi-mi:“MI:0915”(physical association)	0.560
KLK8	NOTCH2NLC	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	KLK8	psi-mi:“MI:0915”(physical association)	0.560
KLK8	KRTAP1-1	psi-mi:“MI:0915”(physical association)	0.560
KLK8	KRT31	psi-mi:“MI:0915”(physical association)	0.560
KLK8	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
KLK8	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
KLK8	KLK6	psi-mi:“MI:0915”(physical association)	0.560
KLK8	TGFBR2	psi-mi:“MI:0915”(physical association)	0.560
KLK8	HTT	psi-mi:“MI:0915”(physical association)	0.560
KLK8	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.510
KLK8	RGS2	psi-mi:“MI:0915”(physical association)	0.370
KLK8	MT-ND1	psi-mi:“MI:0914”(association)	0.350

BioGRID (48): KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), KLK8 (Two-hybrid), KLK8 (Affinity Capture-Western), ATP4A (Affinity Capture-MS), RAB39B (Affinity Capture-MS), RAB39A (Affinity Capture-MS), DDX19B (Affinity Capture-MS), ND1 (Affinity Capture-MS), ARF5 (Affinity Capture-MS), SLC1A4 (Affinity Capture-MS), LMF1 (Affinity Capture-MS), TAMM41 (Affinity Capture-MS), SLC2A8 (Affinity Capture-MS), ATP4A (Affinity Capture-MS)

ESM2 similar proteins: A7WPL7, O43240, O46683, O60259, O88780, P07288, P09582, P09650, P10144, P15944, P19236, P20151, P20718, P21842, P23946, P24158, P33619, P49862, P50341, P50342, P51124, P52195, P56435, P79204, P80219, P83748, Q03238, Q07276, Q14B24, Q28773, Q61096, Q61955, Q6DT45, Q6IE59, Q6UWY2, Q76B45, Q7JIG6, Q92876, Q9BQR3, Q9BZJ3

Diamond homologs: A0A126GUP6, A0A182C2Z2, A0A1S4H5M5, A8JUP7, B5U2W0, B7YZU2, F5HKX0, O15393, O35453, O60235, O60259, O97366, P00774, P03951, P03952, P05049, P05981, P08419, P09871, P10323, P13582, P14272, P21902, P23578, P25155, P26262, P28175, P29293, P31394, P33587, P35035, P35036, P35037, P35039, P35041, P35045, P35046, P35047, P40313, P48038

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	5	18.6×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1124 predictions. Top by Δscore:

Variant	Effect	Δscore
19:51000038:T:TA	donor_gain	1.0000
19:51000085:TTGG:T	donor_gain	1.0000
19:51001092:CCTCA:C	donor_loss	0.9900
19:51001093:CTCAC:C	donor_loss	0.9900
19:51001094:TCACC:T	donor_loss	0.9900
19:51001095:CA:C	donor_loss	0.9900
19:51001096:AC:A	donor_loss	0.9900
19:51001097:C:T	donor_loss	0.9900
19:51002488:T:C	donor_gain	0.9900
19:50997881:TTCT:T	acceptor_gain	0.9800
19:50997883:CT:C	acceptor_gain	0.9800
19:51000020:AG:A	donor_gain	0.9800
19:51000255:TTTC:T	acceptor_gain	0.9800
19:51002493:CAG:C	donor_gain	0.9800
19:51000100:G:A	donor_gain	0.9700
19:51000259:CT:C	acceptor_loss	0.9700
19:51000260:T:C	acceptor_loss	0.9700
19:51001200:G:T	acceptor_gain	0.9700
19:50997885:C:CC	acceptor_gain	0.9600
19:51000259:C:CC	acceptor_gain	0.9600
19:51001560:A:AC	donor_gain	0.9600
19:51001561:C:CC	donor_gain	0.9600
19:51002530:A:AC	donor_gain	0.9600
19:51002531:C:CC	donor_gain	0.9600
19:50997746:CTCA:C	donor_loss	0.9500
19:50997747:TCA:T	donor_loss	0.9500
19:50997748:CACCT:C	donor_loss	0.9500
19:50997749:A:AG	donor_loss	0.9500
19:50997750:C:T	donor_loss	0.9500
19:50999990:CACTA:C	donor_loss	0.9500

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000068735 (19:50999555 G>A), RS1000654907 (19:50995598 G>A), RS1000817589 (19:51001444 G>A), RS1001267336 (19:51000694 G>A,T), RS1002002669 (19:50995708 A>C), RS1002068708 (19:51002576 C>T), RS1002248789 (19:51002313 T>TC), RS1002613355 (19:51001622 G>A), RS1002677113 (19:51002282 G>A), RS1002997671 (19:50996932 A>C), RS1003093124 (19:50997514 G>A), RS1003111635 (19:50997148 G>A,C), RS1003293162 (19:51003600 CCTT>C), RS1003920413 (19:50999308 G>A), RS1004501281 (19:50999056 T>A)

Disease associations

OMIM: gene MIM:605644 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_2842	Blood protein levels	5.000000e-09
GCST006585_334	Blood protein levels	2.000000e-17

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4812 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 32 [PMID: 31675166]	Inhibition	6.7	pIC50

ChEMBL bioactivities

23 potent at pChembl≥5 of 25 total, top 23 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.20	IC50	6.31	nM	CHEMBL4558285
7.60	IC50	25.12	nM	CHEMBL4447752
7.50	IC50	31.62	nM	CHEMBL4465265
7.00	IC50	100	nM	CHEMBL4517343
6.90	IC50	125	nM	CHEMBL239331
6.77	IC50	170	nM	CHEMBL239535
6.77	IC50	170	nM	CHEMBL3770794
6.70	IC50	199.5	nM	CHEMBL4436048
6.68	IC50	210	nM	CHEMBL4206734
6.60	IC50	251.2	nM	CHEMBL4535907
6.60	IC50	251.2	nM	CHEMBL4461533
6.50	IC50	316.2	nM	CHEMBL4543039
6.40	IC50	398.1	nM	CHEMBL4579813
6.10	IC50	790	nM	CHEMBL238707
6.10	IC50	794.3	nM	CHEMBL4530083
5.94	IC50	1160	nM	CHEMBL1184949
5.84	IC50	1440	nM	CHEMBL3771081
5.80	IC50	1585	nM	CHEMBL4460168
5.70	IC50	1995	nM	CHEMBL4473069
5.30	IC50	5000	nM	CHEMBL238913
5.10	IC50	7943	nM	CHEMBL4464120
5.00	IC50	1e+04	nM	CHEMBL4536142
5.00	IC50	1e+04	nM	GRASSYSTATIN A

PubChem BioAssay actives

17 with measured affinity, of 31 total; 17 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
4-[(3R)-1-hydroxy-7-(trifluoromethyl)-3,4-dihydro-2,1-benzoxaborinin-3-yl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.0063	uM
4-[1-hydroxy-7-(trifluoromethyl)-3,4-dihydro-2,1-benzoxaborinin-3-yl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.0251	uM
4-[(3S)-1-hydroxy-7-(trifluoromethyl)-3,4-dihydro-2,1-benzoxaborinin-3-yl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.0316	uM
2-[(3-chlorophenyl)methoxy]-4-(1-hydroxy-3,4-dihydro-2,1-benzoxaborinin-3-yl)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.1000	uM
4-[(1-hydroxy-3H-2,1-benzoxaborol-3-yl)methyl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.1995	uM
[2-[(3,5-dimethyl-1-phenylpyrazol-4-yl)amino]-2-oxoethyl] 2-(6-carbamimidoyl-2-methyl-1H-indol-3-yl)acetate	1387155: Inhibition of KLK8 (unknown origin) expressed in Pichia pastoris pre-incubated for 10 mins before Boc-ValProArg-AMC substrate addition and measured after 30 mins by fluorescence based assay	ic50	0.2100	uM
4-(6-chloro-7-fluoro-1-hydroxy-3,4-dihydro-2,1-benzoxaborinin-3-yl)-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.2512	uM
2-[(2-chlorophenyl)methoxy]-4-(1-hydroxy-3,4-dihydro-2,1-benzoxaborinin-3-yl)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.2512	uM
4-[(6-fluoro-1-hydroxy-3H-2,1-benzoxaborol-3-yl)methyl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.3162	uM
4-(1-hydroxy-3,4-dihydro-2,1-benzoxaborinin-3-yl)-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	0.3981	uM
4-[(5-phenyl-1H-imidazol-2-yl)methylamino]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide	1589834: Inhibition of recombinant C-terminal 10-His tagged human KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate after 40 mins by fluorescence intensity assay	ic50	0.7943	uM
4-(1-hydroxy-8-methyl-3,4-dihydro-2,1-benzoxaborinin-3-yl)-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	1.5849	uM
4-[[1-hydroxy-6-(trifluoromethyl)-3H-2,1-benzoxaborol-3-yl]methyl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	1.9953	uM
4-(7-fluoro-1-hydroxy-3,4-dihydro-2,1-benzoxaborinin-3-yl)-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	7.9433	uM
4-[(1-hydroxy-5-methyl-3H-2,1-benzoxaborol-3-yl)methyl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide;hydrochloride	1601463: Inhibition of recombinant human C-terminal 10-His-tagged KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate incubated for 40 mins by FLINT assay	ic50	10.0000	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S,3R)-2-[[(3S,4S)-4-[[(2S)-4-amino-2-[[(2S)-2-[[(2R)-2-[(2S)-2-[(2S)-2-(dimethylamino)-3-methylbutanoyl]oxy-3-methylbutanoyl]oxy-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxy-6-methylheptanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	448891: Inhibition of kallikrein 8 after 10 to 15 mins by fluorescence assay	ic50	10.0000	uM
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	732087: Inhibition of Kallikrein-8 (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

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Panobinostat	affects cotreatment, affects expression, increases expression	3
Valproic Acid	affects expression, decreases expression, increases methylation	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	affects cotreatment, increases expression	2
Cisplatin	affects cotreatment, affects expression, affects response to substance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
chymostatin	decreases activity	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
trichostatin A	increases expression	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
nickel sulfate	decreases activity	1
leupeptin	decreases activity	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
Aldehydes	increases expression	1
Antipain	decreases activity	1
Arsenic	decreases expression, increases abundance	1
Arsenicals	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	increases expression	1
Calcitriol	increases expression	1
Calcium	increases activity	1
Calcium Chloride	increases activity	1
Diazinon	increases methylation	1
Magnesium	increases activity	1
Magnesium Sulfate	increases activity	1

ChEMBL screening assays

12 unique, capped per target: 11 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1039262	Binding	Inhibition of kallikrein 8 after 10 to 15 mins by fluorescence assay	Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. — J Med Chem
CHEMBL4388474	ADMET	Inhibition of recombinant C-terminal 10-His tagged human KLK8 (Gln29 to Gly260 residues) expressed in mouse NS0 cells using BOC-VPR-AMC as substrate after 40 mins by fluorescence intensity assay	Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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