PRSS8

Summary

PRSS8 (serine protease 8, HGNC:9491) is a protein-coding gene on chromosome 16p11.2, encoding Prostasin (Q16651). Possesses a trypsin-like cleavage specificity with a preference for poly-basic substrates. It is a selective cancer dependency (DepMap: 62.9% of cell lines).

This gene encodes a member of the peptidase S1 or chymotrypsin family of serine proteases. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate via a disulfide bond to form the heterodimeric enzyme. This enzyme is highly expressed in prostate epithelia and is one of several proteolytic enzymes found in seminal fluid. This protease exhibits trypsin-like substrate specificity, cleaving protein substrates at the carboxyl terminus of lysine or arginine residues. The encoded protease partially mediates proteolytic activation of the epithelial sodium channel, a regulator of sodium balance, and may also play a role in epithelial barrier formation.

Source: NCBI Gene 5652 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ichthyosis (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 41 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 62.9% of screened cell lines
• MANE Select transcript: NM_002773

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9491
Approved symbol	PRSS8
Name	serine protease 8
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	CAP1
Ensembl gene	ENSG00000052344
Ensembl biotype	protein_coding
OMIM	600823
Entrez	5652

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000317508, ENST00000564025, ENST00000567531, ENST00000567797, ENST00000567833, ENST00000568261, ENST00000964168

RefSeq mRNA: 1 — MANE Select: NM_002773 NM_002773

CCDS: CCDS45469

Canonical transcript exons

ENST00000317508 — 6 exons

Exon	Start	End
ENSE00000675944	31132429	31132595
ENSE00000675945	31132682	31132953
ENSE00001257144	31131433	31132335
ENSE00001349429	31133226	31133388
ENSE00003487726	31135414	31135727
ENSE00003505181	31135154	31135171

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 98.95.

FANTOM5 (CAGE): breadth broad, TPM avg 34.3050 / max 827.4411, expressed in 593 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157141	28.4629	584
157140	5.8421	486

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.95	gold quality
lower esophagus mucosa	UBERON:0035834	98.89	gold quality
minor salivary gland	UBERON:0001830	97.04	gold quality
ileal mucosa	UBERON:0000331	97.01	gold quality
body of pancreas	UBERON:0001150	96.96	gold quality
skin of abdomen	UBERON:0001416	96.73	gold quality
skin of leg	UBERON:0001511	96.31	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.25	gold quality
saliva-secreting gland	UBERON:0001044	96.22	gold quality
esophagus mucosa	UBERON:0002469	96.06	gold quality
corpus epididymis	UBERON:0004359	95.89	gold quality
rectum	UBERON:0001052	95.53	gold quality
mouth mucosa	UBERON:0003729	95.53	gold quality
duodenum	UBERON:0002114	95.52	gold quality
right lung	UBERON:0002167	95.28	gold quality
gall bladder	UBERON:0002110	95.09	gold quality
zone of skin	UBERON:0000014	94.11	gold quality
left lobe of thyroid gland	UBERON:0001120	94.10	gold quality
colonic mucosa	UBERON:0000317	93.87	gold quality
upper lobe of left lung	UBERON:0008952	93.66	gold quality
metanephros cortex	UBERON:0010533	93.65	gold quality
jejunal mucosa	UBERON:0000399	93.51	gold quality
right lobe of thyroid gland	UBERON:0001119	93.40	gold quality
upper lobe of lung	UBERON:0008948	93.38	gold quality
upper arm skin	UBERON:0004263	93.21	silver quality
mucosa of sigmoid colon	UBERON:0004993	92.80	gold quality
thyroid gland	UBERON:0002046	92.54	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.96	gold quality
pancreas	UBERON:0001264	91.44	gold quality
adult mammalian kidney	UBERON:0000082	91.38	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-MTAB-10885	yes	1205.64
E-MTAB-10855	yes	1164.15
E-MTAB-5061	yes	903.47
E-MTAB-9841	yes	768.33
E-MTAB-8530	yes	248.70
E-MTAB-10662	yes	164.26
E-MTAB-6701	yes	85.44
E-MTAB-10287	yes	44.62
E-GEOD-81547	yes	26.51
E-MTAB-8410	yes	23.62
E-HCAD-10	yes	18.88
E-MTAB-6678	yes	17.74
E-HCAD-1	yes	8.50
E-MTAB-9388	yes	6.86
E-MTAB-3929	no	653.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKBIA, SNAI2, SREBF2

miRNA regulators (miRDB)

33 targeting PRSS8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-5088-5P	97.97	64.28	487
HSA-MIR-5699-3P	97.81	65.00	861
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-1910-5P	97.42	66.36	844
HSA-MIR-10400-3P	97.29	64.66	597
HSA-MIR-4674	97.29	64.62	597
HSA-MIR-6748-3P	97.20	65.66	836
HSA-MIR-4529-5P	96.74	65.77	569
HSA-MIR-500B-3P	96.49	65.40	1087
HSA-MIR-4264	96.35	64.76	1480
HSA-MIR-103B	95.51	66.85	441

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 62.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• protease-mediated regulation of sodium absorption is a function of human airway epithelia, and prostasin is a likely candidate for this activity. (PMID:11756432)
• prostasin is a major regulator of ENaC-mediated Na+ current in DeltaF508 cystic fibrosis epithelia (PMID:15246975)
• prostasin is a channel activating protease; analysis of its substrate specificity (PMID:15474520)
• HAI-1B is a potential physiological regulator of prostasin function (PMID:16103126)
• Dihydrotestosterone regulates prostasin expression in prostate cells via sterol-regulatory element-binding protein stimulation and SLUG repression of prostasin promoter (PMID:16541421)
• The PRSS8 gene was shown to effectively separate these two tumor(chromophobe renal cell carcinoma (RCC) and benign oncocytoma) groups by quantitative reverse transcription-PCR using fresh tissue samples, with similar trends seen on formalin-fixed tissues. (PMID:17145811)
• Data show that prostasin induces protease-dependent and independent molecular changes in the human prostate carcinoma cell line PC-3. (PMID:17532063)
• reduced activity of a matriptase-prostasin proteolytic cascade is the etiological origin of human ARIH and provides an important mouse model for the exploration of matriptase function in ARIH (PMID:17940283)
• prostasin, an upstream prostasin-activating protease, and PN-1 regulate Na+ absorption in the airway and that abnormal prostasin expression contributes to excessive proteolytic activation of ENaC in cystic fibrosis patients (PMID:18310226)
• Genetic variation of the prostasin gene may be implicated in the development of hypertension in youths. (PMID:18583984)
• crystallographic analysis of prostasin (PMID:18922802)
• Suggest that urinary prostasin could be a novel biomarker and/or mechanism for renal pressure natriuresis in normotensive black adolescents. (PMID:19127211)
• it is not clear, at the present time, whether endogenous aldosterone regulates prostasin expression or vice versa (PMID:19262497)
• study presents structures of the extracellular domain of active prostasin in several forms; of particular interest is the S1 subsite loop which opens and closes in response to basic residues or divalent ions, directly binding Ca(+2) cations (PMID:19388054)
• the mRNA level of PN-1 is significantly elevated in colorectal cancer tissue (PMID:19555470)
• prostasin is overexpressed in many epithelial ovarian cancers; a potential tumor marker (PMID:19606239)
• In the in vitro cultured human choriocarcinomal JEG-3 cells, treatment with functional antibody against prostasin led to promotion in cell invasion capability, as well as increase in the production of MMP-2, MMP-26, TIMP-1, and TIMP-4. (PMID:19847458)
• Loss of prostasin expression in bladder transitional cell carcinomas is associated with epithelial-mesenchymal transition. (PMID:19849847)
• Hepsin activates prostasin and cleaves the extracellular domain of the epidermal growth factor receptor. (PMID:19911255)
• Essential hypertension in Xinjiang Kazakhs is not associated with the 2827C>T polymorphism in the prostasin gene. (PMID:20078940)
• Prostasin may regulate trophoblast cell proliferation via modulating the EGFR-MAPK signaling pathway. (PMID:20089521)
• Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. (PMID:20204133)
• the matriptase-prostasin proteolytic cascade is tightly regulated by two mechanisms: 1) prostasin activation temporally coupled to matriptase autoactivation and 2) HAI-1 rapidly inhibiting not only active matriptase but also active prostasin (PMID:20696767)
• Transport via the transcytotic pathway makes prostasin available as a substrate for matriptase. (PMID:21148558)
• Expression of matriptase and prostasin is closely correlated in breast cancer cell lines and in breast cancer tissues. Matriptase and prostasin display a near identical spatial expression pattern in the epithelial compartment of breast cancer tissue. (PMID:21678412)
• Study does not provide evidence of a major role of prostasin variation in blood pressure modulation. (PMID:21933610)
• prostasin is present, mature and active on the apical surface of wild-type and cystic fibrosis bronchial epithelial cells (PMID:22582115)
• urinary prostasin correlates with the aldosterone to renin ratio, and it is physiologically modulated by natriuresis in normotensive individuals (PMID:23344129)
• Prostasin requires expression of endogenous matriptase to stimulate barrier formation since matriptase depletion by siRNA silencing abrogates prostasin barrier-forming activity. (PMID:23443662)
• prostasin is a non-enzymatic co-factor for matriptase activation (PMID:23673661)
• Our study suggested that Axl and prostasin expression may be closely related to carcinogenesis, metastasis, and prognosis of ovarian adenocarcinoma. (PMID:23707658)
• Prostasin repress cancer cells and contribute to chemoresistance by modulating the CASP/PAK2-p34/actin pathway. (PMID:24434518)
• The higher frequency of C allele of prostasin gene at rs12597511 is associated with severe preeclampsia. (PMID:24890150)
• Prostasin regulate the Lin28/Let-7 loop in ovarian cancer cells. (PMID:25188517)
• In urinary exosomes, NCC and prostasin had a diurnal pattern parallel to ADH and aquaporin 2, confirming that, in healthy subjects, both prostasin and NCC relate to water balance. (PMID:25931204)
• Polymorphism of the prostasin gene is closely associated with poor pregnancy outcomes of early-onset severe preeclampsia. (PMID:26252104)
• It is concluded that prostasin protein level change is less likely to be causally involved in placental dysfunction in preeclampsia. (PMID:26867056)
• Overexpression of PRSS8 mRNA and high levels of prostasin in multiple subtypes of early stage ovarian tumors may provide clinical biomarkers for early detection of ovarian cancer. (PMID:27036110)
• PRSS8 acts as a tumor suppressor in colorectal cancer (PMID:27050145)
• Data show that PRSS8 was reduced in esophageal squamous cell carcinomas (ESCC) tissues and the reduction of PRSS8 was associated with poor differentiation and shorter survival time. (PMID:27081034)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Prss8	ENSMUSG00000030800
rattus_norvegicus	Prss8	ENSRNOG00000019616

Protein

Protein identifiers

Prostasin — Q16651 (reviewed: Q16651)

Alternative names: Channel-activating protease 1, Serine protease 8

All UniProt accessions (3): Q16651, H3BUJ8, H3BVC8

UniProt curated annotations — full annotation on UniProt →

Function. Possesses a trypsin-like cleavage specificity with a preference for poly-basic substrates. Stimulates epithelial sodium channel (ENaC) activity through activating cleavage of the gamma subunits (SCNN1G).

Subunit / interactions. Heterodimer of two chains, light and heavy, held by a disulfide bond.

Subcellular location. Cell membrane Secreted. Extracellular space Secreted. Extracellular space.

Tissue specificity. Found in prostate, liver, salivary gland, kidney, lung, pancreas, colon, bronchus and renal proximal tubular cells. In the prostate gland it may be synthesized in epithelial cells, secreted into the ducts, and excreted into the seminal fluid.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16651-1	1	yes
Q16651-2	2

RefSeq proteins (1): NP_002764* (*=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.B6 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (44 total): strand 17, helix 6, disulfide bond 5, active site 3, chain 3, turn 3, propeptide 2, signal peptide 1, glycosylation site 1, splice variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
3GYL	X-RAY DIFFRACTION	1.3
3DFJ	X-RAY DIFFRACTION	1.45
3E16	X-RAY DIFFRACTION	1.6
3FVF	X-RAY DIFFRACTION	1.6
3E0N	X-RAY DIFFRACTION	1.7
3E0P	X-RAY DIFFRACTION	1.7
3E1X	X-RAY DIFFRACTION	1.7
3DFL	X-RAY DIFFRACTION	2
3GYM	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16651-F1	84.49	0.66

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): 238 (charge relay system); 85 (charge relay system); 134 (charge relay system)

Disulfide bonds (5): 37–154, 70–86, 168–244, 201–223, 234–262

Glycosylation sites (1): 159

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope

MSigDB gene sets: 450 (showing top): MODULE_172, DAVIES_MULTIPLE_MYELOMA_VS_MGUS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_MSN, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, ATACCTC_MIR202, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MORF_HDAC1, HSIAO_HOUSEKEEPING_GENES

GO Biological Process (2): proteolysis (GO:0006508), positive regulation of sodium ion transport (GO:0010765)

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

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
regulation of sodium ion transport	1
sodium ion transport	1
positive regulation of monoatomic ion transport	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
membrane	1
cell periphery	1
extracellular vesicle	1

Protein interactions and networks

STRING

1076 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRSS8	SPINT1	O43278	842
PRSS8	SPINT2	O43291	700
PRSS8	SCNN1G	P51170	662
PRSS8	SCNN1A	P37088	657
PRSS8	NEDD4L	Q96PU5	605
PRSS8	FURIN	P09958	604
PRSS8	NEDD4	P46934	578
PRSS8	ASIC2	Q16515	564
PRSS8	SERPINE2	P07093	550
PRSS8	KAT8	Q9H7Z6	478
PRSS8	SCNN1B	P51168	462
PRSS8	TJP3	O95049	435
PRSS8	CFTR	P13569	428
PRSS8	IRF6	O14896	427
PRSS8	ZNF157	P51786	426

IntAct

65 interactions, top by confidence:

A	B	Type	Score
MAD2L1	INSR	psi-mi:“MI:0914”(association)	0.700
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
IL27RA	AP1G2	psi-mi:“MI:0914”(association)	0.530
PRSS8	BRAF	psi-mi:“MI:2364”(proximity)	0.470
BRAF	PRSS8	psi-mi:“MI:0915”(physical association)	0.470
PRSS8	ATF7IP	psi-mi:“MI:0915”(physical association)	0.370
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350
rs27_rs27l_human	HBD	psi-mi:“MI:0914”(association)	0.350
KLK15	SPINT1	psi-mi:“MI:0914”(association)	0.350
PRSS8	GPAA1	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
ANLN	UBA6	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350
IARS1	TARS3	psi-mi:“MI:0914”(association)	0.350
UPK2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SGCA	TMEM131L	psi-mi:“MI:0914”(association)	0.350
GZMH	DENND11	psi-mi:“MI:0914”(association)	0.350
LYZL2	POTEF	psi-mi:“MI:0914”(association)	0.350
CFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
EDN3	POTEF	psi-mi:“MI:0914”(association)	0.350
FNDC5	A2ML1	psi-mi:“MI:0914”(association)	0.350
SLC25A6	A2ML1	psi-mi:“MI:0914”(association)	0.350
SPINT2		psi-mi:“MI:0914”(association)	0.350
B3GALT4		psi-mi:“MI:0914”(association)	0.350
BRINP2	MANBA	psi-mi:“MI:0914”(association)	0.350
PRTN3	MANBA	psi-mi:“MI:0914”(association)	0.350

BioGRID (63): PRSS8 (Affinity Capture-MS), SRC (Negative Genetic), PRSS8 (Negative Genetic), PRSS8 (Negative Genetic), PRSS8 (Negative Genetic), PRSS8 (Positive Genetic), PRSS8 (Positive Genetic), PRSS8 (Affinity Capture-MS), PRSS8 (PCA), PRSS8 (Affinity Capture-MS), MICA (Affinity Capture-MS), ERF (Affinity Capture-MS), TUBA1B (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS)

ESM2 similar proteins: A1L453, A2VE36, A6NIE9, A8MTI9, E5RG02, O35453, O70169, P08709, P20231, P21845, P50343, P83748, Q14B25, Q14BX2, Q15661, Q16651, Q2F9P2, Q2F9P4, Q2UVH8, Q3UKY7, Q3V0Q7, Q402U7, Q571E5, Q5FBW1, Q5FBW2, Q5M8S2, Q6AXZ6, Q6BEA2, Q6IE62, Q6IE63, Q6UWB4, Q76HL1, Q7RTY5, Q7Z410, Q7Z5A4, Q8BJR6, Q8K4I7, Q8VIF2, Q920S2, Q99MS4

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.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

851 predictions. Top by Δscore:

Variant	Effect	Δscore
16:31132423:GCTTA:G	donor_loss	1.0000
16:31132425:TTA:T	donor_loss	1.0000
16:31132426:TACC:T	donor_loss	1.0000
16:31132428:C:CG	donor_loss	1.0000
16:31132592:CTCA:C	acceptor_gain	1.0000
16:31132593:TCA:T	acceptor_gain	1.0000
16:31132594:CA:C	acceptor_gain	1.0000
16:31132594:CAC:C	acceptor_gain	1.0000
16:31132595:AC:A	acceptor_loss	1.0000
16:31132596:C:CC	acceptor_gain	1.0000
16:31132596:C:CG	acceptor_loss	1.0000
16:31132677:CTCA:C	donor_loss	1.0000
16:31132679:CACCT:C	donor_loss	1.0000
16:31132680:A:T	donor_loss	1.0000
16:31132949:GCTCG:G	acceptor_gain	1.0000
16:31132950:CTCG:C	acceptor_gain	1.0000
16:31132950:CTCGC:C	acceptor_gain	1.0000
16:31132951:TCG:T	acceptor_gain	1.0000
16:31132951:TCGC:T	acceptor_loss	1.0000
16:31132951:TCGCT:T	acceptor_gain	1.0000
16:31132952:CG:C	acceptor_gain	1.0000
16:31132952:CGC:C	acceptor_gain	1.0000
16:31132953:GCTGC:G	acceptor_loss	1.0000
16:31132954:C:CC	acceptor_gain	1.0000
16:31132954:CTG:C	acceptor_loss	1.0000
16:31135411:TAC:T	donor_loss	1.0000
16:31132427:A:AC	donor_gain	0.9900
16:31132428:C:CC	donor_gain	0.9900
16:31132428:CCTGG:C	donor_gain	0.9900
16:31132598:G:C	acceptor_gain	0.9900

AlphaMissense

2207 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:31132701:C:A	W173C	1.000
16:31132701:C:G	W173C	1.000
16:31132267:C:A	W258C	0.999
16:31132267:C:G	W258C	0.999
16:31132433:C:G	C234S	0.999
16:31132434:A:T	C234S	0.999
16:31132466:C:G	C223S	0.999
16:31132467:A:T	C223S	0.999
16:31132532:C:T	C201Y	0.999
16:31132703:A:G	W173R	0.999
16:31132703:A:T	W173R	0.999
16:31133234:G:C	C86W	0.999
16:31133318:C:A	W58C	0.999
16:31133318:C:G	W58C	0.999
16:31132201:C:A	W280C	0.998
16:31132201:C:G	W280C	0.998
16:31132270:G:C	S257R	0.998
16:31132270:G:T	S257R	0.998
16:31132272:T:G	S257R	0.998
16:31132325:C:A	G239V	0.998
16:31132325:C:T	G239E	0.998
16:31132326:C:A	G239W	0.998
16:31132331:T:A	D237V	0.998
16:31132433:C:T	C234Y	0.998
16:31132466:C:T	C223Y	0.998
16:31132467:A:G	C223R	0.998
16:31132532:C:G	C201S	0.998
16:31132533:A:T	C201S	0.998
16:31132700:C:A	G174C	0.998
16:31132716:G:C	C168W	0.998

dbSNP variants (sampled 300 via entrez): RS1000861170 (16:31133352 C>G,T), RS1000892251 (16:31132915 G>T), RS1001486863 (16:31134611 G>C), RS1002217979 (16:31134040 C>T), RS1002537285 (16:31135520 G>A,C), RS1003783911 (16:31135217 T>C), RS1004787134 (16:31131440 C>G), RS1005336592 (16:31134069 G>T), RS1005612662 (16:31137356 A>G,T), RS1005726392 (16:31137301 A>C,G), RS1005841412 (16:31136961 G>A), RS1006554697 (16:31134133 T>A,C), RS1007445827 (16:31135788 G>A), RS1007509982 (16:31135549 G>A,T), RS1007747164 (16:31133606 C>T)

Disease associations

OMIM: gene MIM:600823 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
ichthyosis	Moderate	Autosomal recessive

Mondo (1): ichthyosis (MONDO:0019269)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008103_175	Bipolar disorder	8.000000e-06
GCST008115_45	Bipolar I disorder	5.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009963	bipolar I disorder

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5610 (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
B3C	Inhibition	7.92	pKi

ChEMBL bioactivities

22 potent at pChembl≥5 of 24 total, top 22 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	Ki	12	nM	CHEMBL505558
7.72	Ki	19	nM	CHEMBL500474
7.57	Ki	27	nM	CHEMBL505738
7.55	Ki	28	nM	CHEMBL505048
7.54	Ki	29	nM	CHEMBL476038
7.40	Ki	40	nM	CHEMBL498914
7.39	Ki	41	nM	CHEMBL443101
7.35	Ki	45	nM	CHEMBL506226
7.31	Ki	49	nM	CHEMBL509770
7.22	Ki	60	nM	CHEMBL500835
7.19	Ki	65	nM	CHEMBL446259
7.00	Ki	101	nM	CHEMBL504789
6.89	Ki	130	nM	CHEMBL448873
6.75	Ki	176	nM	CHEMBL501945
6.57	Ki	267	nM	CHEMBL454436
6.29	Ki	510	nM	CHEMBL510406
5.98	Ki	1040	nM	CHEMBL507245
5.85	Ki	1400	nM	CHEMBL501802
5.81	Ki	1550	nM	CHEMBL501405
5.68	Ki	2100	nM	CHEMBL503925
5.24	Ki	5720	nM	CHEMBL507205
5.24	Ki	5780	nM	CHEMBL504394

PubChem BioAssay actives

22 with measured affinity, of 26 total; 22 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
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-[(4-chlorophenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0120	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-(cyclohexylmethoxy)pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0190	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-[(4-fluorophenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0270	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-[[4-(trifluoromethyl)phenyl]methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0280	uM
[(3R,5S)-5-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-1-[(2R)-4-phenyl-2-(phenylmethoxycarbonylamino)butanoyl]pyrrolidin-3-yl] piperidine-1-carboxylate	409756: Binding affinity to human prostasin	ki	0.0290	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-phenylmethoxypyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0400	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-[[3-(trifluoromethyl)phenyl]methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0410	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0450	uM
benzyl N-[(2R)-1-[(2S,3S)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-3-methylpyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0490	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-(benzylcarbamoyloxy)pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0600	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-(cyclopentylmethoxy)pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.0650	uM
[(3R,5S)-5-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-1-[(2R)-4-phenyl-2-(phenylmethoxycarbonylamino)butanoyl]pyrrolidin-3-yl] pyrrolidine-1-carboxylate	409756: Binding affinity to human prostasin	ki	0.1010	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-(phenylcarbamoyloxy)pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.1300	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-[(4-methylsulfonylphenyl)methylcarbamoyloxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.1760	uM
benzyl N-[(2R)-1-[(2S,3R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-3-phenylpyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	0.2670	uM
[(3R,5S)-5-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-1-[(2R)-4-phenyl-2-(phenylmethoxycarbonylamino)butanoyl]pyrrolidin-3-yl] morpholine-4-carboxylate	409756: Binding affinity to human prostasin	ki	0.5100	uM
benzyl N-[(2R)-1-[(2S,4R)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-4-hydroxypyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	1.0400	uM
benzyl N-[(2R)-1-[(2S)-2-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	1.4000	uM
[(3R,5S)-5-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]carbamoyl]-1-[(2R)-4-phenyl-2-(phenylmethoxycarbonylamino)butanoyl]pyrrolidin-3-yl] N,N-dimethylcarbamate	409756: Binding affinity to human prostasin	ki	1.5500	uM
benzyl N-[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]amino]-1-oxo-4-phenylbutan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	2.1000	uM
benzyl N-[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	5.7200	uM
benzyl N-[(2S)-6-amino-1-[[(2S)-1-[[(2S)-6-amino-1-(1,3-benzoxazol-2-yl)-1-oxohexan-2-yl]amino]-1-oxo-4-phenylbutan-2-yl]amino]-1-oxohexan-2-yl]carbamate	409756: Binding affinity to human prostasin	ki	5.7800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	6
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	3
Estradiol	affects cotreatment, decreases expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
afuresertib	increases expression	1
bisphenol A	affects expression	1
lead acetate	decreases expression	1
afimoxifene	decreases expression, decreases reaction	1
cupric chloride	decreases expression	1
nickel sulfate	increases expression	1
octa-2,4,6-trienoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
LG 100815	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Cadmium	increases expression	1
Copper	decreases expression, affects binding	1
Coumestrol	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Disulfiram	affects binding, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6110325	Binding	Inhibition of prostasin (unknown origin)	Small molecule inhibitors of mannan-binding lectin-associated serine Proteases-2 and-3. — Eur J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1LI	Abcam Jurkat PRSS8 KO	Cancer cell line	Male
CVCL_D1Q7	Abcam K-562 PRSS8 KO	Cancer cell line	Female
CVCL_D2LT	Abcam Raji PRSS8 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis
NCT03051347	Not specified	COMPLETED	Asthma and Atopic Dermatitis Validation of PROMIS Pediatric Instruments
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT03464994	Not specified	COMPLETED	Ophthalmological Abnormalities in Hereditary Ichthyosis (ICHTYO-KERATO)
NCT03641261	Not specified	COMPLETED	Therapeutic Education Using an Internet Application in Hereditary Ichthyosis
NCT03796052	Not specified	COMPLETED	Study Determining Safety and Efficacy of Avena Sativa (Oat) Skincare Products for Treating Skin Dryness and Itching in Cancer Patients
NCT05610306	Not specified	COMPLETED	Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06123091	Not specified	UNKNOWN	Exploring Patient Reported Outcomes in Inherited Ichthyosis
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07066150	Not specified	COMPLETED	A Clinical Evaluation of Marula-Derived Ceramide Cream on Skin Barrier Function Enhancement