CTSS

Summary

CTSS (cathepsin S, HGNC:2545) is a protein-coding gene on chromosome 1q21.3, encoding Cathepsin S (P25774). Thiol protease.

The preproprotein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that participates in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The mature protein cleaves the invariant chain of MHC class II molecules in endolysosomal compartments and enables the formation of antigen-MHC class II complexes and the proper display of extracellular antigenic peptides by MHC-II. The mature protein also functions as an elastase over a broad pH range. When secreted from cells, this protein can remodel components of the extracellular matrix such as elastin, collagen, and fibronectin. This gene is implicated in the pathology of many inflammatory and autoimmune diseases and, given its elastase activity, plays a significant role in some pulmonary diseases. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 1520 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 28 total
• GTEx eGene: eQTL in 47 tissues, sQTL in 3 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug; 12 molecules with ChEMBL bioactivity (top 3% of genes corpus-wide)
• Constraint (gnomAD): pLI 0.19 (intermediate), LOEUF 0.66 (unconstrained)
• MANE Select transcript: NM_004079
• Interaction hub: 3,816 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2545
Approved symbol	CTSS
Name	cathepsin S
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163131
Ensembl biotype	protein_coding
OMIM	116845
Entrez	1520

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 15 protein_coding, 8 nonsense_mediated_decay, 4 retained_intron

MANE Select: ENST00000368985

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 1, TSL 5: 2

ENST00000368985, ENST00000448301, ENST00000472977, ENST00000480760, ENST00000483930, ENST00000607427, ENST00000679512, ENST00000679582, ENST00000679898, ENST00000680288, ENST00000680311, ENST00000680466, ENST00000680471, ENST00000680664, ENST00000680931, ENST00000681357, ENST00000681444, ENST00000681728, ENST00000681863, ENST00000857595, ENST00000857596, ENST00000962999, ENST00000963000, ENST00001019166, ENST00001092431, ENST00001092432, ENST00001140621

RefSeq mRNA: 2 — MANE Select: NM_004079 NM_001199739, NM_004079

CCDS: CCDS55634, CCDS968

Canonical transcript exons

ENST00000368985 — 8 exons

Exon	Start	End
ENSE00001448523	150764638	150764764
ENSE00001874248	150730188	150733145
ENSE00001922877	150765698	150765778
ENSE00003459282	150757858	150757980
ENSE00003464542	150751781	150752008
ENSE00003525779	150755001	150755150
ENSE00003698961	150750006	150750171
ENSE00003699493	150747777	150747879

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 99.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 160.5591 / max 5514.8933, expressed in 1057 samples.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, granulocyte, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CTSS is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 47 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 50 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	7.1e-70	+0.47	1:150753762:C:T
Cells Cultured fibroblasts	eqtl	2.6e-47	+0.39	1:150773930:G:T
Esophagus Mucosa	eqtl	5.0e-30	+0.28	1:150751271:T:C
Artery Tibial	eqtl	1.0e-28	-0.43	1:150713240:T:C
Adipose Subcutaneous	eqtl	2.7e-28	-0.41	1:150764744:A:G
Cells EBV-transformed lymphocytes	eqtl	1.2e-26	+0.42	1:150790663:G:A
Muscle Skeletal	eqtl	1.7e-25	+0.30	1:150771016:T:C
Testis	eqtl	2.5e-23	+0.43	1:150781011:G:A
Skin Sun Exposed Lower leg	eqtl	3.7e-23	+0.24	1:150842935:G:A
Brain Cerebellum	eqtl	7.6e-22	+0.66	1:150773930:G:T
Esophagus Muscularis	eqtl	2.6e-21	+0.29	1:150752859:G:T
Heart Atrial Appendage	eqtl	1.2e-20	+0.27	1:150825272:T:C
Liver	eqtl	2.7e-20	+0.40	1:150642618:A:C
Stomach	eqtl	3.5e-19	+0.23	1:150958986:G:A
Pancreas	eqtl	3.4e-18	+0.25	1:150826101:C:G
Skin Not Sun Exposed Suprapubic	eqtl	3.0e-17	+0.26	1:150753762:C:T
Brain Cerebellar Hemisphere	eqtl	1.1e-16	+0.50	1:150794346:G:A
Nerve Tibial	eqtl	1.5e-15	+0.22	1:150756200:T:C
Breast Mammary Tissue	eqtl	1.8e-14	+0.23	1:150753762:C:T
Adipose Visceral Omentum	eqtl	2.3e-14	-0.33	1:150764744:A:G

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
14353	123.9158	897
14354	35.6134	879
14350	0.8576	223
14345	0.0898	39
14346	0.0826	38

Top tissues by expression

showing 100 of 283 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.94	gold quality
mononuclear cell	CL:0000842	99.93	gold quality
leukocyte	CL:0000738	99.92	gold quality
granulocyte	CL:0000094	99.66	gold quality
blood	UBERON:0000178	99.40	gold quality
rectum	UBERON:0001052	99.28	gold quality
bone marrow cell	CL:0002092	99.14	gold quality
gall bladder	UBERON:0002110	98.60	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.55	gold quality
colonic mucosa	UBERON:0000317	98.45	gold quality
vermiform appendix	UBERON:0001154	98.43	gold quality
bone marrow	UBERON:0002371	98.34	gold quality
colonic epithelium	UBERON:0000397	98.25	gold quality
trabecular bone tissue	UBERON:0002483	98.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.04	gold quality
bronchial epithelial cell	CL:0002328	97.94	gold quality
mucosa of transverse colon	UBERON:0004991	97.88	gold quality
spleen	UBERON:0002106	97.87	gold quality
right lung	UBERON:0002167	97.64	gold quality
lymph node	UBERON:0000029	97.09	gold quality
epithelium of bronchus	UBERON:0002031	96.89	gold quality
upper lobe of left lung	UBERON:0008952	96.83	gold quality
epithelium of nasopharynx	UBERON:0001951	96.73	gold quality
upper lobe of lung	UBERON:0008948	96.66	gold quality
ileal mucosa	UBERON:0000331	96.41	gold quality
bronchus	UBERON:0002185	96.37	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.24	gold quality
palpebral conjunctiva	UBERON:0001812	96.10	gold quality
tonsil	UBERON:0002372	95.98	gold quality
lower lobe of lung	UBERON:0008949	95.97	gold quality
transverse colon	UBERON:0001157	95.57	gold quality
jejunal mucosa	UBERON:0000399	95.48	gold quality
nasal cavity mucosa	UBERON:0001826	95.36	gold quality
visceral pleura	UBERON:0002401	95.35	gold quality
right uterine tube	UBERON:0001302	95.25	gold quality
caecum	UBERON:0001153	95.09	gold quality
duodenum	UBERON:0002114	94.87	gold quality
right coronary artery	UBERON:0001625	94.53	gold quality
lung	UBERON:0002048	94.46	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.39	gold quality
small intestine	UBERON:0002108	93.95	gold quality
nasal cavity epithelium	UBERON:0005384	93.95	gold quality
calcaneal tendon	UBERON:0003701	93.67	gold quality
decidua	UBERON:0002450	92.95	gold quality
pleura	UBERON:0000977	92.66	gold quality
intestine	UBERON:0000160	92.34	gold quality
smooth muscle tissue	UBERON:0001135	92.29	gold quality
omental fat pad	UBERON:0010414	92.07	gold quality
peritoneum	UBERON:0002358	92.01	gold quality
islet of Langerhans	UBERON:0000006	91.93	gold quality
large intestine	UBERON:0000059	91.88	gold quality
periodontal ligament	UBERON:0008266	91.85	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.74	gold quality
amniotic fluid	UBERON:0000173	91.64	gold quality
colon	UBERON:0001155	91.59	gold quality
descending thoracic aorta	UBERON:0002345	91.23	gold quality
epithelial cell of pancreas	CL:0000083	91.18	gold quality
urinary bladder	UBERON:0001255	91.07	gold quality
parietal pleura	UBERON:0002400	91.04	gold quality
superficial temporal artery	UBERON:0001614	90.88	gold quality
minor salivary gland	UBERON:0001830	90.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.36	gold quality
layer of synovial tissue	UBERON:0007616	89.64	gold quality
adipose tissue	UBERON:0001013	89.43	gold quality
liver	UBERON:0002107	89.43	gold quality
body of stomach	UBERON:0001161	89.28	gold quality
saliva-secreting gland	UBERON:0001044	89.25	gold quality
connective tissue	UBERON:0002384	89.25	gold quality
germinal epithelium of ovary	UBERON:0001304	89.22	gold quality
right adrenal gland cortex	UBERON:0035827	88.74	gold quality
left coronary artery	UBERON:0001626	88.63	gold quality
stomach	UBERON:0000945	88.59	gold quality
skin of hip	UBERON:0001554	88.57	gold quality
thoracic aorta	UBERON:0001515	88.56	gold quality
mouth mucosa	UBERON:0003729	88.39	gold quality
ascending aorta	UBERON:0001496	88.25	gold quality
synovial joint	UBERON:0002217	88.12	gold quality
coronary artery	UBERON:0001621	87.82	gold quality
left adrenal gland	UBERON:0001234	87.62	gold quality
right adrenal gland	UBERON:0001233	87.58	gold quality
adrenal gland	UBERON:0002369	87.31	gold quality
mucosa of urinary bladder	UBERON:0001259	87.04	gold quality
esophagus mucosa	UBERON:0002469	87.02	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.88	gold quality
left adrenal gland cortex	UBERON:0035825	86.52	gold quality
placenta	UBERON:0001987	86.43	gold quality
upper leg skin	UBERON:0004262	86.16	gold quality
oral cavity	UBERON:0000167	86.10	gold quality
pancreas	UBERON:0001264	86.08	gold quality
thoracic mammary gland	UBERON:0005200	85.83	gold quality
mammary gland	UBERON:0001911	85.70	gold quality
adrenal cortex	UBERON:0001235	85.60	gold quality
sigmoid colon	UBERON:0001159	85.55	gold quality
adrenal tissue	UBERON:0018303	85.51	gold quality
pancreatic ductal cell	CL:0002079	85.21	silver quality
left uterine tube	UBERON:0001303	85.07	gold quality
right lobe of liver	UBERON:0001114	84.91	gold quality
mammary duct	UBERON:0001765	84.89	gold quality
spinal cord	UBERON:0002240	84.67	gold quality
tendon	UBERON:0000043	84.42	gold quality

Single-cell (SCXA)

Detected in 37 experiment(s), a significant marker in 36.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	7318.71
E-GEOD-150728	yes	5484.29
E-GEOD-130148	yes	4533.69
E-MTAB-9221	yes	3576.48
E-GEOD-149689	yes	3386.94
E-MTAB-10432	yes	2877.22
E-MTAB-8498	yes	2678.91
E-MTAB-8207	yes	2555.86
E-HCAD-4	yes	2485.78
E-CURD-126	yes	2311.73
E-CURD-112	yes	2238.45
E-MTAB-6701	yes	2218.07
E-HCAD-32	yes	2125.78
E-HCAD-15	yes	2114.85
E-MTAB-10553	yes	2002.71

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	164.0
Spleen	tissue	127.8	high
Frontal cortex	tissue	126.5
Bone marrow	tissue	122.0	high
Appendix	tissue	82.4
Colon	tissue	78.1	high
Lung	tissue	69.8	high
Lymph node	tissue	66.5	high
Small intestine	tissue	60.0	high
Duodenum	tissue	55.5	high
Rectum	tissue	55.2	high
Spinal cord	tissue	54.1
Urinary bladder	tissue	40.0	medium
Stomach 1	tissue	39.9	medium
Liver	tissue	37.6	low
Tonsil	tissue	35.8	high
Substantia nigra	tissue	35.4
Midbrain	tissue	31.6
Medulla oblongata	tissue	30.6
Pons	tissue	30.4
Superior colliculi	tissue	30.4
Corpus callosum	tissue	29.4
Hypothalamus	tissue	26.7
Gallbladder	tissue	26.7	high
Periaqueductal gray	tissue	24.4
Thalamus	tissue	24.3
Putamen	tissue	22.6
Septum	tissue	22.2
Placenta	tissue	22.0	not detected
Adipose tissue	tissue	19.6	not detected
Amygdala	tissue	18.9
Hippocampal formation	tissue	18.8
Ventral forebrain	tissue	18.8
Thymus	tissue	18.6
Choroid plexus	tissue	17.6
Olfactory bulb	tissue	17.0
Basal ganglia	tissue	16.8	not detected
Entorhinal cortex	tissue	16.1
Salivary gland	tissue	16.0	medium
Cerebral cortex	tissue	15.2	high
Insular cortex	tissue	15.2
Breast	tissue	14.9	not detected
Temporal cortex	tissue	14.8
Motor cortex	tissue	14.7
Smooth muscle	tissue	14.6	not detected
Adrenal gland	tissue	14.3	not detected
Retrosplenial cortex	tissue	14.2
Retrosplenial and cingulate cortex	tissue	13.6
Fallopian tube	tissue	13.6	high
Prefrontal cortex	tissue	13.5
Occipital cortex	tissue	12.7
Somatosensory cortex	tissue	12.6
Cerebellum	tissue	11.8	not detected
Locus coeruleus	tissue	11.6
Hippocampus	tissue	10.0	low
Esophagus	tissue	9.8	not detected
Nucleus accumbens	tissue	9.0
Cervix	tissue	8.6	low
Tongue	tissue	8.3
Thyroid gland	tissue	7.3	low

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Dorsal spinal cord (54.1), Ventral spinal cord (43.2), Lateral funiculus (white matter) (36.3), White matter (29.4), Nucleus gracilis (26.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF1, IRF2, NGF, PPARG, SPI1

miRNA regulators (miRDB)

Targeting CTSS by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 108 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929

Functional genomics

gnomAD constraint: pLI 0.195, LOEUF 0.664, missense Z 2.69 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000368985 — one region, missense o/e 0.63.

Literature-anchored findings (GeneRIF, showing 40)

• Cathepsin S activity is detectable in human keratinocytes and is selectively upregulated upon stimulation with interferon-gamma. (PMID:12164923)
• the subcellular distribution of cathepsin B, L, and S activities underwent a shift from endosome to lysosome localization during monocyte differentiation in cell culture (PMID:12437117)
• an additional sorting motif in procathepsin S besides the classical Man-6-P recognition signal (PMID:12643447)
• Cathepsin S activity is required for efficient surface display of MHC class II in myoblasts from patients with inflammatory myopathies and on myoblasts stimulated by IFN-gamma. (PMID:12742663)
• cathepsin S efficiently degrades MHC class II-associated invariant chain in nonprofessional antigen-presenting cells (PMID:12748383)
• Data show that CatS expression is up-regulated in astrocytoma cells and provide evidence for a potential role for CatS in invasion. (PMID:12819022)
• in contrast with results from dendritic cells, inhibition of CatS activity prevented N-terminal processing of invariant chain Ii but did not alter the subcellular trafficking or surface delivery of class II complexes (PMID:14966190)
• Cathepsin S may have a significant influence on human atherogenesis. (PMID:16140306)
• The presence of active cathepsins L, K and S suggests that they contribute to the extracellular breakdown of the extracellular matrix. (PMID:16354158)
• The decrease in CTSS concentrations in the circulation may contribute to vascular improvement in obese subjects after weight loss. (PMID:16394095)
• plays an important role in atherosclerotic plaque destabilization and rupture (PMID:16410454)
• cathepsin S may serve as a useful prognostic indicator and potential target for anti-invasive therapy (PMID:16550604)
• CTSS released locally by preadipocytes promotes adipogenesis, suggesting a possible contribution of this protease to fat mass expansion in obesity (PMID:16825321)
• non-fat cells in human adipose tissue contribute to most of the release of cathepsin S seen during primary culture of adipose tissue explants from obese women (PMID:16839849)
• Crystal structure of the active-site mutant Cys25 –> Ala of glycosylated human procathepsin S. (PMID:17075137)
• analysis of human cathepsins K, L, and S iunteractions with elastins (PMID:17227755)
• secretory leukocyte protease inhibitor can inhibit interferon-gamma-induced cathepsin S production by macrophages (PMID:17878156)
• Four novel functional polymorphisms were identified in the cathepsin S gene, in the 5–flaning region, which has a possible association with pulmonary emphysema in Japanese patients. (PMID:18410260)
• evidence that CTSS sequence variations are associated with two human metabolic risk factors for cardiovascular diseases: plasma Apo-A1 and HDL-C concentrations. (PMID:18565099)
• analysis of cathepsin S activity in antigen presenting cells using a novel specific substrate (PMID:18957408)
• radiation induced CatS expression via ROS-IFN-gamma pathways, and this increased expression may be involved in radioresistance (PMID:19101991)
• CIITA transfection did not induce cathepsin S, an important protease responsible for the degradation of the invariant chain, and thus for binding of the peptides to the MHC class II binding groove (PMID:19104823)
• In contrast to cathepsin S, cathepsin H values did not correlate with markers of inflammation, indicating a specific role for cathepsin H in the pleural host response. (PMID:19404922)
• A significantly higher number of cathepsin S expressing macrophages was found in castration-resistant than in hormone naive high grade tumours in patients. (PMID:19487544)
• cathepsin S is necessary for invariant chain proteolysis in T cells; CD4(+)HLA-DR(+) T cells down-regulated cathepsin S expression (PMID:19553543)
• The researchers found no evidence of an association between the CTSS -25G/A polymorphism and the presence of coronary artery disease in a Chinese population. (PMID:19593952)
• U87 tumour cells significantly enhance the proliferation of co-cultured endothelial cells by a mechanism involving cathepsin B, but not cathepsin S (PMID:19700239)
• Our data provide first evidence that Cathepsin S expression is selectively induced in psoriatic keratinocytes. (PMID:19849712)
• Results describe a sensitive and selective cathepsin S substrate that permits continuous measurement of the enzymatic activity even in crude tissue extracts. (PMID:20045715)
• In humans, cathepsin S is more influenced than cathepsins L and K by changes in energy balance in adipose tissue and circulation (PMID:20164293)
• cathepsin S was found to be significantly elevated in rheumatoid arthritis and osteoarthritis synovial fluid. (PMID:20180636)
• the immunosuppressive effects of IL-10-STAT3 on MHC-II antigen presentation may occur via the inhibition of cathepsin S expres (PMID:20356901)
• Data show that plasma levels of cathepsin S mRNA, but not cathepsin B mRNA, are increased in patients with coronary atherosclerosis. (PMID:20880494)
• These data indicate that cathepsins B, L and S may act as cell-death mediators in in monocytic cells infected with ICP4 and Us3 deletion mutant herpes simplex virus type 1. (PMID:20881085)
• Down-regulation of cathepsin S was found in inverted papilloma tissues as compared with its expression level in normal sinus mucosa tissues. (PMID:21038029)
• Cathepsin S activity in human whole blood was dependent on the time of blood collection, suggesting that cathepsin S activity is subject to circadian variations. (PMID:21094118)
• We investigated the modulation of Cathepsin S, Cathepsin B and Cystatin C expression in immune cells by interferon (IFN)-beta, and their role in cell migration (PMID:21112096)
• results suggest that cathepsin S and cystatin C may contribute to disease activity in multiple sclerosis, specifically in a subgroup of patients that are responsive to IFN-beta therapy (PMID:21143385)
• results suggest that CTSS mediated atherogenesis may be associated with a CD40 mediated inflammatory and immune response. Further invasive atheroma analysis is reasonable (PMID:21223957)
• Serum cathepsin S showed significantly lower values 4 days after surgery (PMID:21250859)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctss2.2	ENSDARG00000013771
danio_rerio	ctss2.1	ENSDARG00000074656
mus_musculus	Ctss	ENSMUSG00000038642
rattus_norvegicus	Ctss	ENSRNOG00000021157
caenorhabditis_elegans		WBGENE00000781
caenorhabditis_elegans		WBGENE00000782
caenorhabditis_elegans		WBGENE00000784
caenorhabditis_elegans		WBGENE00000785
caenorhabditis_elegans		WBGENE00013072
caenorhabditis_elegans		WBGENE00013076
caenorhabditis_elegans		WBGENE00013764
caenorhabditis_elegans		WBGENE00016300
caenorhabditis_elegans		WBGENE00016306
caenorhabditis_elegans		WBGENE00019314
caenorhabditis_elegans		WBGENE00019986
caenorhabditis_elegans		WBGENE00022189
caenorhabditis_elegans		WBGENE00044760

Paralogs (12): CTSZ (ENSG00000101160), CTSH (ENSG00000103811), CTSC (ENSG00000109861), CTSL (ENSG00000135047), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:107341) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 24 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased IgG level	2
dystrophic muscle	1
hyperglycemia	1
abnormal humoral immune response	1
decreased IgM level	1
salivary gland inflammation	1
abnormal T cell physiology	1
abnormal professional antigen presenting cell physiology	1
abnormal B lymphocyte antigen presentation	1
abnormal B cell physiology	1
increased hematocrit	1
abnormal cytokine secretion	1
decreased susceptibility to induced arthritis	1
abnormal vascular endothelial cell physiology	1
insulitis	1
decreased susceptibility to autoimmune diabetes	1
decreased susceptibility to experimental autoimmune myasthenia gravis	1
decreased spleen weight	1
decreased angiogenesis	1
abnormal interleukin secretion	1
centrally nucleated skeletal muscle fibers	1
skeletal muscle fibrosis	1
impaired exercise endurance	1
impaired humoral immune response	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	P61276	100.0%	Diamond
Macaca mulatta	P61277	100.0%	Diamond
Ananas macrodontes	P83447	100.0%	Diamond
Oryza sativa Indica Group	A2XQE8	99.7%	Diamond
Bos taurus	P25975	99.7%	Diamond
Oryza sativa Japonica Group	Q7XWK5	99.7%	Diamond
Rachiplusia ou MNPV (strain R1)	Q8B9D5	99.1%	Diamond
Actinidia deliciosa	A5HII1	98.4%	Diamond
Actinidia chinensis var. chinensis	P00785	98.4%	Diamond
Pongo abelii	Q5R6D1	98.2%	Diamond
Vanilla planifolia	A0A0F7G352	98.0%	Diamond
Canis lupus familiaris	Q3ZKN1	96.4%	Diamond
Sus scrofa	Q9GLE3	96.4%	Diamond
Chlorocebus aethiops	Q9GKL8	96.1%	Diamond
Oryctolagus cuniculus	P43236	95.8%	Diamond
Ovis aries	P83205	94.6%	Diamond
Salvelinus alpinus	Q70SU7	94.4%	Diamond
Salmo salar	Q70SU8	94.4%	Diamond
Paramecium tetraurelia	A0E358	94.3%	Diamond
Saimiri boliviensis boliviensis	Q8HY82	94.0%	Diamond
Vigna mungo	P12412	93.1%	Diamond
Phaseolus vulgaris	P25803	93.1%	Diamond
Vasconcellea cundinamarcensis	P32957	93.0%	Diamond
Tabernaemontana divaricata	A5YVK8	91.3%	Diamond
Carica papaya	P05993	90.0%	Diamond
Zea mays	Q10717	88.8%	Diamond
Arabidopsis thaliana	Q9SUS9	88.4%	Diamond
Brassica napus	P25251	87.7%	Diamond
Hordeum vulgare	P05167	87.0%	Diamond
Ananas comosus	O23791	86.2%	Diamond
Dermatophagoides farinae	P16311	86.0%	Diamond
Giardia duodenalis	P92132	82.9%	Diamond
Ricinus communis	O65039	82.8%	Diamond
Jacaratia mexicana	P84346	81.9%	Diamond
Choristoneura fumiferana DEF multiple nucleopolyhedrovirus	Q6VTL7	91.7%	Diamond
Antheraea pernyi nucleopolyhedrovirus	Q91CL9	91.7%	Diamond
Choristoneura fumiferana multiple nucleopolyhedrovirus	P41715	90.1%	Diamond
Hyphantria cunea nucleopolyhedrovirus	Q9WGE0	85.8%	Diamond
Mamestra configurata nucleopolyhedrovirus A	Q8QLK1	84.8%	Diamond
Spodoptera exigua nuclear polyhedrosis virus (strain US)	Q9J8B9	84.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CTSK	protein-coding	1513
ARNT	protein-coding	405
HORMAD1	protein-coding	84072
GOLPH3L	protein-coding	55204
ENSA	protein-coding	2029

Protein

Protein identifiers

Cathepsin S — P25774 (reviewed: P25774)

All UniProt accessions (12): A0A7P0T7Z6, A0A7P0T844, P25774, A0A7P0T8A1, A0A7P0T8H4, A0A7P0T8U1, A0A7P0T904, A0A7P0TAQ0, A0A7P0TB77, A0A804DAZ0, U3KPS4, U3KQE7

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules and MHC class II antigen presentation. The bond-specificity of this proteinase is in part similar to the specificities of cathepsin L. Elicits itch by mediating cleavage and activation of MRGPRX1.

Subunit / interactions. Monomer.

Subcellular location. Lysosome. Secreted. Cytoplasmic vesicle. Phagosome.

Similarity. Belongs to the peptidase C1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P25774-1	1	yes
P25774-2	2

RefSeq proteins (2): NP_001186668, NP_004070* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000169	Pept_cys_AS	Active_site
IPR000668	Peptidase_C1A_C	Domain
IPR013128	Peptidase_C1A	Family
IPR013201	Prot_inhib_I29	Domain
IPR025660	Pept_his_AS	Active_site
IPR025661	Pept_asp_AS	Active_site
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR039417	Peptidase_C1A_papain-like	Domain

Pfam: PF00112, PF08246

Enzyme classification (BRENDA)

• EC 3.4.22.27 — cathepsin S (BRENDA: 16 organisms, 211 substrates, 1033 inhibitors, 84 Km, 41 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-VAL-VAL-ARG-7-AMIDO-4-METHYLCO	0.006–0.288	10
BENZYLOXYCARBONYL-LEU-ARG-7-AMIDO-4-METHYLCOUMAR	0.0171–0.0534	6
BENZYLOXYCARBONYL-PHE-ARG-7-AMIDO-4-METHYLCOUMAR	0.0147–0.042	5
BENZYLOXYCARBONYL-PHE-VAL-ARG-7-AMIDO-4-METHYLCO	0.0121–0.0125	2
(4-METHYL-7-[[(2S)-2-(4-[(1S)-1-(4-METHYLCYCLOHE	0.017	1
(7-METHOXYCOUMARIN-4-YL)-ACETYL-GRWPPMGLPWEK(2,4	0.0056	1
(7-[[(2S)-2-(4-[(1S)-1,2-DIMETHYL-1-[(PHENYLCARB	0.41	1
(7-[[(2S)-2-(4-[(1S)-1,2-DIMETHYL-1-[(THIOPHEN-3	0.3	1
(7-[[(2S)-2-(4-[(1S)-1-CYCLOHEXYL-1-[(PHENYLCARB	0.057	1
(7-[[(2S)-2-(4-[(1S)-1-CYCLOHEXYL-1-[(THIOPHEN-3	0.13	1
BENZOYL-PHE-VAL-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0081	1
BENZYLOXYCARBONYL-LEU-LEU-ARG-7-AMIDO-4-METHYLCO	0.0034	1
GRWH-NORLEUCINE-VGLRWE-LYS(2,4-DINITROPHENYL)-D-	0.0016	1
GRWHDVGLRWE-LYS(2,4-DINITROPHENYL)-D-ARG-NH2	0.0019	1
GRWHFVGLRWE-LYS(2,4-DINITROPHENYL)-D-ARG-NH2	0.0014	1

UniProt features (49 total): helix 18, strand 12, disulfide bond 4, active site 3, turn 3, sequence variant 2, signal peptide 1, propeptide 1, splice variant 1, mutagenesis site 1, sequence conflict 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

showing 30 of 62 structures by resolution:

PDB	Title	Method	Resolution (Å)
9GJ2	Crystal structure of human cathepsin S produced in insect cells in complex with ketoamide …	X-RAY DIFFRACTION	1.15
6YYR	Structure of Cathepsin S in complex with Compound 20b	X-RAY DIFFRACTION	1.3
3OVX	Cathepsin S in complex with a covalent inhibitor with an aldehyde warhead	X-RAY DIFFRACTION	1.49
2H7J	Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.	X-RAY DIFFRACTION	1.5
6YYO	Structure of Cathepsin S in complex with Compound 1	X-RAY DIFFRACTION	1.5
2HHN	Cathepsin S in complex with non covalent arylaminoethyl amide.	X-RAY DIFFRACTION	1.55
8RND	Cathepsin S in complex with NNPI-C10 inhibitor	X-RAY DIFFRACTION	1.56
4P6G	Crystal Structure of Human Cathepsin S Bound to a Non-covalent Inhibitor.	X-RAY DIFFRACTION	1.58
2FRQ	Human Cathepsin S with Inhibitor CRA-26871	X-RAY DIFFRACTION	1.6
2OP3	The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by …	X-RAY DIFFRACTION	1.6
3N3G	4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not …	X-RAY DIFFRACTION	1.6
2FQ9	Cathepsin S with nitrile inhibitor	X-RAY DIFFRACTION	1.65
2FT2	Human Cathepsin S with Inhibitor CRA-29728	X-RAY DIFFRACTION	1.7
8PI3	Cathepsin S Y132D mutant in complex with NNPI-C10 inhibitor	X-RAY DIFFRACTION	1.73
5QC8	Crystal structure of human Cathepsin-S with bound ligand	X-RAY DIFFRACTION	1.74
5QBV	Crystal structure of human Cathepsin-S with bound ligand	X-RAY DIFFRACTION	1.8
1NQC	Crystal structures of Cathepsin S inhibitor complexes	X-RAY DIFFRACTION	1.8
2HH5	Crystal Structure of Cathepsin S in complex with a Zinc mediated non-covalent …	X-RAY DIFFRACTION	1.8
4P6E	Crystal Structure of Human Cathepsin S Bound to a Non-covalent Inhibitor	X-RAY DIFFRACTION	1.8
5QCC	Crystal structure of human Cathepsin-S with bound ligand	X-RAY DIFFRACTION	1.8
1MS6	Dipeptide Nitrile Inhibitor Bound to Cathepsin S.	X-RAY DIFFRACTION	1.9
2F1G	Cathepsin S in complex with non-covalent 2-(Benzoxazol-2-ylamino)-acetamide	X-RAY DIFFRACTION	1.9
2FRA	Human Cathepsin S with CRA-27934, a Nitrile Inhibitor	X-RAY DIFFRACTION	1.9
2HXZ	Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor (Hexagonal …	X-RAY DIFFRACTION	1.9
3N4C	6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors	X-RAY DIFFRACTION	1.9
5QC0	Crystal structure of human Cathepsin-S with bound ligand	X-RAY DIFFRACTION	1.9
5QC7	Crystal structure of human Cathepsin-S with bound ligand	X-RAY DIFFRACTION	1.9
2FUD	Human Cathepsin S with Inhibitor CRA-27566	X-RAY DIFFRACTION	1.95
5QCD	Crystal structure of human Cathepsin-S with bound ligand	X-RAY DIFFRACTION	1.95
2R9M	Cathepsin S complexed with Compound 15	X-RAY DIFFRACTION	1.97

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25774-F1	94.51	0.89

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH supported · IF approved

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)

Position	Role
139
278
298

Disulfide bonds (4)

Type	Positions
Disulfide bond	272–320, 126–224, 136–180, 170–213

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	104

Mutagenesis-validated functional residues (1)

Position	Phenotype
104	abolishes glycosylation.

Function

Pathways and Gene Ontology

Reactome pathways

7 curated (TAS) of 25; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

25 pathways:

ID	Pathway	Evidence
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures	curated
R-HSA-9766229	Degradation of CDH1	curated
R-HSA-2132295	MHC class II antigen presentation	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-9979719	Processing of antigen in germinal center B cells	curated
R-HSA-9958810	SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	curated
R-HSA-1679131	Trafficking and processing of endosomal TLR	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-418990	Adherens junctions interactions	—
R-HSA-1236975	Antigen processing-Cross presentation	—
R-HSA-446728	Cell junction organization	—
R-HSA-1500931	Cell-Cell communication	—
R-HSA-421270	Cell-cell junction organization	—
R-HSA-983169	Class I MHC mediated antigen processing & presentation	—
R-HSA-1474290	Collagen formation	—
R-HSA-1474228	Degradation of the extracellular matrix	electronic
R-HSA-1236977	Endosomal/Vacuolar pathway	electronic
R-HSA-1474244	Extracellular matrix organization	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-9764265	Regulation of CDH1 Expression and Function	—
R-HSA-9764561	Regulation of CDH1 Function	—
R-HSA-9764274	Regulation of Expression and Function of Type I Classical Cadherins	—
R-HSA-9759476	Regulation of Homotypic Cell-Cell Adhesion	—
R-HSA-168898	Toll-like Receptor Cascades	—

MSigDB gene sets: 444 (showing top): MODULE_172, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, GOBP_POSITIVE_REGULATION_OF_CATION_CHANNEL_ACTIVITY, SWEET_KRAS_ONCOGENIC_SIGNATURE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOCC_SECRETORY_GRANULE, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, MODULE_45, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOZGIT_ESR1_TARGETS_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (17): toll-like receptor signaling pathway (GO:0002224), adaptive immune response (GO:0002250), regulation of antigen processing and presentation (GO:0002577), proteolysis (GO:0006508), immune response (GO:0006955), response to acidic pH (GO:0010447), protein processing (GO:0016485), antigen processing and presentation (GO:0019882), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), extracellular matrix disassembly (GO:0022617), collagen catabolic process (GO:0030574), basement membrane disassembly (GO:0034769), antigen processing and presentation of peptide antigen (GO:0048002), cellular response to thyroid hormone stimulus (GO:0097067), positive regulation of cation channel activity (GO:2001259), protein catabolic process (GO:0030163), sensory perception of itch (GO:0160025)

GO Molecular Function (10): fibronectin binding (GO:0001968), cysteine-type endopeptidase activity (GO:0004197), serine-type endopeptidase activity (GO:0004252), collagen binding (GO:0005518), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), laminin binding (GO:0043236), proteoglycan binding (GO:0043394), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (11): extracellular region (GO:0005576), lysosome (GO:0005764), late endosome (GO:0005770), extracellular matrix (GO:0031012), endolysosome lumen (GO:0036021), lysosomal lumen (GO:0043202), phagocytic vesicle (GO:0045335), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

14 top-level categories:

Category	Pathways
Extracellular matrix organization	2
Innate Immune System	2
Immune System	2
Antigen processing-Cross presentation	1
Toll-like Receptor Cascades	1
Collagen formation	1
Adaptive Immune System	1
Regulation of CDH1 Function	1
Activation of STAT3 by cadherin engagement	1
Affinity selection of immunoglobulins	1
Class I MHC mediated antigen processing & presentation	1
Cell-cell junction organization	1
Cell junction organization	1
Cell-Cell communication	1

GO top-level categories

52 GO namespaces:

Category	Terms
protein binding	3
antigen processing and presentation	2
protein metabolic process	2
immune system process	2
endopeptidase activity	2
cellular anatomical structure	2
intracellular organelle lumen	2
pattern recognition receptor signaling pathway	1
immune response	1
regulation of immune system process	1
response to stimulus	1
response to pH	1
proteolysis	1
protein maturation	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
cellular component disassembly	1
extracellular matrix organization	1
catabolic process	1
collagen metabolic process	1
extracellular matrix disassembly	1
basement membrane organization	1
cellular response to hormone stimulus	1
response to thyroid hormone	1
monoatomic cation channel activity	1
positive regulation of ion transmembrane transporter activity	1
positive regulation of cation transmembrane transport	1
macromolecule catabolic process	1
sensory perception	1
cysteine-type peptidase activity	1
serine-type peptidase activity	1
protein-containing complex binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
extracellular matrix binding	1
carbohydrate derivative binding	1
binding	1
catalytic activity	1
lytic vacuole	1
endosome	1
external encapsulating structure	1
endosome lumen	1
endolysosome	1
lysosomal lumen	1
lysosome	1
vacuolar lumen	1
endocytic vesicle	1
tertiary granule	1
ficolin-1-rich granule	1
cytoplasm	1
intracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 21 of 40 annotations. The rest are phylogenetic / computational / electronic (IEA).

21 experimentally-supported GO terms:

GO term	NS	Evidence
adaptive immune response	BP	expression pattern
antigen processing and presentation of exogenous peptide antigen via MHC class II	BP	direct assay
antigen processing and presentation of peptide antigen	BP	direct assay
basement membrane disassembly	BP	direct assay
cellular response to thyroid hormone stimulus	BP	expression pattern
collagen catabolic process	BP	direct assay
positive regulation of cation channel activity	BP	direct assay
protein processing	BP	direct assay
proteolysis	BP	direct assay
regulation of antigen processing and presentation	BP	direct assay
response to acidic pH	BP	direct assay
extracellular matrix	CC	high-throughput assay
late endosome	CC	direct assay
lysosome	CC	direct assay
phagocytic vesicle	CC	direct assay
collagen binding	MF	direct assay
cysteine-type endopeptidase activity	MF	direct assay
cysteine-type peptidase activity	MF	direct assay
fibronectin binding	MF	physical interaction
laminin binding	MF	direct assay
proteoglycan binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 3,816 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSS	CTSD	P07339	869
CTSS	LGMN	Q99538	865
CTSS	CST3	P01034	849
CTSS	CSTB	P04080	825
CTSS	CSTA	P01040	822
CTSS	TMPRSS2	O15393	764
CTSS	CD74	P04233	758
CTSS	CTSA	P10619	753
CTSS	FURIN	P09958	750
CTSS	LAMP1	P11279	738
CTSS	TIMP1	P01033	733
CTSS	C1QB	P02746	728
CTSS	ELN	P15502	718
CTSS	CST6	Q15828	713
CTSS	IL1B	P01584	696

IntAct

Human interaction partners of CTSS in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
IRF2	association	0.530	2

BioGRID (222 interactions; top human partners by supporting records): ACTN1 (Affinity Capture-MS; 2 records), ACTN4 (Affinity Capture-MS; 2 records), AIF1L (Affinity Capture-MS; 2 records), BAG2 (Affinity Capture-MS; 2 records), BAG5 (Affinity Capture-MS; 2 records), CALR (Affinity Capture-MS; 2 records), CALU (Affinity Capture-MS; 2 records), CKAP4 (Affinity Capture-MS; 2 records), CNPY2 (Affinity Capture-MS; 2 records), CNPY3 (Affinity Capture-MS; 2 records), COLGALT1 (Affinity Capture-MS; 2 records), CPD (Affinity Capture-MS; 2 records), DDOST (Affinity Capture-MS; 2 records), DNAJB11 (Affinity Capture-MS; 2 records), DNAJC10 (Affinity Capture-MS; 2 records)

SIGNOR signaling

5 signaling interactions:

A	Effect	B	Mechanism
CTSS	“up-regulates quantity”	“peptide antigen”	“chemical modification”
CTSS	“down-regulates quantity”	oligopeptide	“chemical modification”
CTSS	up-regulates	ECM_disassembly
CTSS	“down-regulates quantity by destabilization”	BGLAP	cleavage
TFE3	“up-regulates quantity by expression”	CTSS	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for CTSS: 28 ClinVar records (0 pathogenic / likely pathogenic); 13 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	2
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 383):

Position(s)	Effect	Δscore	Sites
1:150750172–150750173	acceptor_loss	1.0000	6
1:150751779–150751780	donor_loss	1.0000	5
1:150757856–150757857	donor_loss	1.0000	5
1:150757982	acceptor_loss	1.0000	2
1:150757988	acceptor_gain	1.0000
1:150764767	acceptor_gain	1.0000
1:150733148	acceptor_gain	0.9900
1:150747775–150747776	donor_loss	0.9900	5
1:150747880–150747881	acceptor_loss	0.9900	6
1:150747889	acceptor_loss	0.9900

AlphaMissense

760 missense substitutions predicted likely pathogenic (of 2,181 scored), across 189 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
N298	8	0.943	0.992
H278	8	0.938	0.964
D82	8	0.933	0.961
D169	8	0.933	0.973
S163	8	0.919	0.994
F142	8	0.899	0.990
S299	8	0.873	0.976
H62	8	0.864	0.962
D253	8	0.840	0.909
W52	7	0.979	0.993
C320	7	0.978	0.992
W294	7	0.977	0.995
W31	7	0.976	0.990
W140	7	0.975	0.994
C170	7	0.973	0.986
W28	7	0.971	0.989
C272	7	0.964	0.981
C180	7	0.958	0.980
F189	7	0.958	0.977
C136	7	0.955	0.976

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Squamous Cell Carcinoma (TCGA)	unfavorable	0.000583
Bladder Urothelial Carcinoma (TCGA)	favorable	0.000646
Pancreatic Adenocarcinoma (validation)	favorable	0.000802
Colon Adenocarcinoma (validation)	favorable	0.000856

Disease associations

OMIM: gene MIM:116845 | disease phenotypes:

GWAS associations

13 associations:

Study	Trait	p-value
GCST006585_689	Blood protein levels	4e-62
GCST011126_5	Caffeine consumption from coffee or tea	1e-26
GCST011126_36	Caffeine consumption from coffee or tea	1e-23
GCST90002389_351	Lymphocyte percentage of white cells	3e-21
GCST90011899_87	Aspartate aminotransferase levels	2e-18
GCST90002395_153	Mean platelet volume	4e-13
GCST90013410_28	Basal cell carcinoma	3e-9
GCST005951_48	Body mass index	4e-9
GCST011125_2	Caffeine consumption from coffee	5e-9
GCST010479_2	Coronary artery disease	9e-9
GCST002226_2	Fat body mass	4e-8
GCST001966_1	Rhegmatogenous retinal detachment	1e-7
GCST003419_2	Congenital left-sided heart lesions	9e-7

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0006781	coffee consumption measurement
EFO:0010091	tea consumption measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111368 (SELECTIVITY GROUP), CHEMBL2954 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CTSS protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
PETESICATIB	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 11,395 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

12 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL218394	BOCEPREVIR	4	2,896
CHEMBL4802135	NIRMATRELVIR	4	1,314
CHEMBL501849	SIMEPREVIR	4	1,880
CHEMBL231813	TELAPREVIR	4	3,453
CHEMBL481611	ODANACATIB	3	828
CHEMBL4525964	VANIPREVIR	3	452
CHEMBL4297638	PETESICATIB	2	46
CHEMBL5095230	ATUZAGINSTAT	2	75
CHEMBL371064	BALICATIB	2	99
CHEMBL5591580	IBUZATRELVIR	2	20
CHEMBL91704	K-777	2	213
CHEMBL203665	RELACATIB	2	119

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C1: Papain

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
petesicatib	Inhibition	10.0	pIC50
VBY-825	Inhibition	9.89	pKi
compound (R)-26 [PMID: 22686657]	Inhibition	9.3	pKi
compound 4d [PMID: 38746883]	Inhibition	9.15	pIC50
LHVS	Inhibition	9.0	pIC50
K11777	Inhibition	8.7	pKi
LY3000328	Inhibition	8.11	pIC50
odanacatib	Inhibition	7.22	pIC50

Binding affinities (BindingDB)

2780 measured of 3377 human assays (3398 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.003 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.003 nM
2-cyano-4-(cyclohexylamino)-N-[2-(3-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	IC50	0.009 nM
2-cyano-4-(cyclohexylamino)-N-(2-phenylethyl)pyrimidine-5-carboxamide	IC50	0.01 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[3-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.011 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.011 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.013 nM
2-cyano-4-(cyclohexylamino)-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	IC50	0.022 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.025 nM
2-cyano-N-[[4-(trifluoromethyl)phenyl]methyl]-4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-5-carboxamide	IC50	0.029 nM	US-8524710: Pyrrolidine derivatives
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{3-[2-(1H-imidazol-1-yl)ethoxy]-4-methoxyphenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.031 nM
2-cyano-4-(cyclohexylamino)-N-{2-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.047 nM
4-[(3S)-3-(2-chloro-4-pyrazol-1-ylphenyl)sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.052 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[2-chloro-4-(4-cyclopropylpiperazin-1-yl)phenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.056 nM	US-8524710: Pyrrolidine derivatives
N-[2-(4-chlorophenyl)propyl]-2-cyano-4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-5-carboxamide	IC50	0.056 nM	US-8524710: Pyrrolidine derivatives
2-cyano-N-(2,2,2-trifluoroethyl)-4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-5-carboxamide	IC50	0.061 nM	US-8524710: Pyrrolidine derivatives
CHEMBL2207565	IC50	0.1 nM
CHEMBL2207564	IC50	0.1 nM
Petesicatib	IC50	0.1 nM
4-[(3S)-3-(2-chloro-4-imidazol-1-ylphenyl)sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.11 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[2-chloro-4-(2-methoxyethoxy)phenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.13 nM	US-8524710: Pyrrolidine derivatives
(2S)-2-(1-benzofuran-2-ylformamido)-4-methyl-N-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)azepan-4-yl]pentanamide	KI	0.14 nM
CHEMBL4596647	IC50	0.149 nM
4-[(3S)-3-[4-(4-tert-butylpiperazin-1-yl)-2-chlorophenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.15 nM	US-8524710: Pyrrolidine derivatives
2-cyano-4-[(3S)-3-(2,3-dichlorophenyl)sulfonylpyrrolidin-1-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-5-carboxamide	IC50	0.155 nM	US-8524710: Pyrrolidine derivatives
4-(trifluoromethyl)-6-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-2-carbonitrile	IC50	0.167 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-carbonitrile	IC50	0.205 nM	US-8524710: Pyrrolidine derivatives
CHEMBL4761229	KI	0.25 nM
CHEMBL4594870	IC50	0.278 nM
(2S,4R)-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-(1-thiomorpholin-4-ylcyclopropanecarbonyl)pyrrolidine-2-carboxamide	IC50	0.3 nM	US-8802665: Pyrrolidine derivatives
(2S,4R)-4-(3-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-(1-piperidin-1-ylcyclopropanecarbonyl)pyrrolidine-2-carboxamide	IC50	0.3 nM	US-8802665: Pyrrolidine derivatives
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[4-(pyrrolidin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.3 nM
CHEMBL2207562	IC50	0.3 nM
N-[[1-(4-chlorophenyl)cyclopropyl]methyl]-2-cyano-4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-5-carboxamide	IC50	0.305 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-2-carbonitrile	IC50	0.31 nM	US-8524710: Pyrrolidine derivatives
2-cyano-4-[(3S)-3-(2,3-dichlorophenyl)sulfonylpyrrolidin-1-yl]-N-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide	IC50	0.32 nM	US-8524710: Pyrrolidine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(2-methyl-3-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.322 nM	US-9409882: Pyridine derivatives
4-[(3S)-3-(2-chloro-4-fluorophenyl)sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.335 nM	US-8524710: Pyrrolidine derivatives
(2S,4R)-4-[4-(5-Methyl-tetrazol-1-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide	IC50	0.349 nM	US-10689339: Pyrrolidine derivatives
4-[(3S)-3-[4-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-chlorophenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.355 nM	US-8524710: Pyrrolidine derivatives
N-{4-[5-(2-Thienyl)-1,2,4-oxadiazol-3-yl]benzoyl}-leucyl-methylazalanine-nitrile	KI	0.36 nM
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.375 nM	US-9409882: Pyridine derivatives
tert-butyl 2-[(2S,4R)-4-(2-chloro-4-fluorophenyl)sulfonyl-2-[(1-cyanocyclopropyl)carbamoyl]pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-2-pyridinyl)azetidine-1-carboxylate	IC50	0.377 nM	US-8822505: Azetidine derivatives
N-(Benzyloxycarbonyl)-tyrosyl-methylazalanine-nitrile	KI	0.38 nM
(2S,4R)-4-[2-chloro-4-(2-methyl-3-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(3-fluoro-5-iodo-2-pyridinyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.382 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-(4-[1,2,3]Triazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide	IC50	0.382 nM	US-10689339: Pyrrolidine derivatives
(2S,4R)-4-(4-(1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide	IC50	0.391 nM	US-10689339: Pyrrolidine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chloro-4-methoxyphenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.393 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.398 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(3-methylpiperidin-1-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.4 nM	US-8802665: Pyrrolidine derivatives

ChEMBL bioactivities

2770 potent at pChembl≥5 of 2904 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.80	Ki	0.016	nM	CHEMBL5573840
10.54	IC50	0.029	nM	CHEMBL3651506
10.41	Ki	0.039	nM	CHEMBL5573840
10.28	IC50	0.052	nM	CHEMBL3651502
10.25	IC50	0.056	nM	CHEMBL3651503
10.25	IC50	0.056	nM	CHEMBL3651507
10.21	IC50	0.061	nM	CHEMBL3651508
10.05	Ki	0.09	nM	CHEMBL4777335
10.00	IC50	0.1	nM	CHEMBL2207565
10.00	IC50	0.1	nM	CHEMBL2207564
10.00	IC50	0.1	nM	PETESICATIB
10.00	Kd	0.1	nM	CHEMBL155560
10.00	Kd	0.1	nM	CHEMBL356442
9.96	IC50	0.11	nM	CHEMBL3651509
9.89	Ki	0.13	nM	CHEMBL3342185
9.89	IC50	0.13	nM	CHEMBL3651505
9.89	IC50	0.13	nM	CHEMBL386506
9.82	IC50	0.15	nM	CHEMBL3651499
9.82	Ki	0.15	nM	CHEMBL1651361
9.81	IC50	0.155	nM	CHEMBL3651510
9.80	Ki	0.16	nM	CHEMBL1651355
9.80	Ki	0.16	nM	CHEMBL1651357
9.78	IC50	0.167	nM	CHEMBL3651495
9.77	Ki	0.17	nM	CHEMBL1651356
9.75	Ki	0.176	nM	CHEMBL3342184
9.72	Ki	0.19	nM	CHEMBL1651349
9.70	IC50	0.2	nM	CHEMBL251117
9.70	IC50	0.2	nM	CHEMBL443319
9.70	IC50	0.2	nM	CHEMBL251719
9.70	Ki	0.2	nM	CHEMBL4777740
9.70	Ki	0.2	nM	CHEMBL1651352
9.70	Ki	0.2	nM	CHEMBL1651354
9.69	IC50	0.205	nM	CHEMBL3651493
9.64	IC50	0.23	nM	CHEMBL385632
9.60	Ki	0.25	nM	CHEMBL4761229
9.59	Ki	0.26	nM	CHEMBL177914
9.53	IC50	0.296	nM	CHEMBL3649369
9.52	IC50	0.3	nM	CHEMBL2207562
9.52	IC50	0.3	nM	CHEMBL3093935
9.52	Ki	0.3	nM	CHEMBL3640716
9.52	IC50	0.305	nM	CHEMBL3651511
9.52	IC50	0.3	nM	CHEMBL3701872
9.52	IC50	0.3	nM	CHEMBL3701887
9.52	IC50	0.3	nM	CHEMBL250720
9.52	IC50	0.3	nM	CHEMBL400750
9.52	IC50	0.3	nM	CHEMBL398553
9.52	Kd	0.3	nM	CHEMBL153813
9.52	Kd	0.3	nM	CHEMBL152940
9.52	Kd	0.3	nM	CHEMBL149523
9.51	IC50	0.31	nM	CHEMBL3651473

PubChem BioAssay actives

2480 with measured affinity, of 3410 total; 50 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
N-[(2S)-3-cyclohexyl-1-oxo-1-[[(2S)-1-oxo-3-phenylmethoxypropan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide	2094804: Inhibition of recombinant Cathepsin S (unknown origin) expressed in Escherichia coli using Z-Val-Val-Arg-AMC as substrate by fluorescence based assay	ki	<0.0001	uM
N-[(2S)-1-[[(1R)-1-cyano-2-phenylmethoxyethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]thiophene-2-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0001	uM
N-[(2S)-1-[[(1R)-1-cyano-2-[(2-methylphenyl)methoxy]ethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0001	uM
tert-butyl N-[cyano-[2-(dibenzylamino)-2-oxoethyl]amino]carbamate	1168919: Inhibition of human cathepsin S using Z-Phe-Arg-AMC fluorogenic substrate fluorogenic substrate incubated for 60 mins	ki	0.0001	uM
2-cyano-4-(cyclohexylamino)-N-(2-phenylethyl)pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0001	uM
N-[(2R)-1-[(1-cyanocyclopropyl)amino]-1-oxo-3-(4-pyridin-2-ylpiperazin-1-yl)sulfonylpropan-2-yl]-3,3-dimethylbutanamide	1675896: Inhibition of recombinant human Cathepsin S expressed in baculovirus infected insect cells using Z-VVR-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 10 mins by fluorescence assay	ki	0.0001	uM
N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-4-(5-thiophen-2-yl-1,2,4-oxadiazol-3-yl)benzamide	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0001	uM
N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-4-methyl-1-oxopentan-2-yl]morpholine-4-carboxamide	370547: Inhibition of human recombinant cathepsin S by fluorescence assay	ki	0.0001	uM
(2S,4R)-N-(1-cyanocyclopropyl)-4-[4-(1-methylpyrazol-4-yl)-2-(trifluoromethyl)phenyl]sulfonyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2094802: Inhibition of Cathepsin S (unknown origin)	ic50	0.0001	uM
N-[(1S)-1-[1-(cyanomethyl)triazol-4-yl]-1-(4-methylcyclohexyl)ethyl]thiophene-3-carboxamide	717412: Inhibition of cathepsin S using FR-aminoluciferin as substrate preincubated for 15 mins before substrate addition measured after 1 hr by luminescence assay	ic50	0.0001	uM
N-[(1S)-1-[1-[(1R)-1-cyanoethyl]triazol-4-yl]-1-(4-methylcyclohexyl)ethyl]thiophene-3-carboxamide	717412: Inhibition of cathepsin S using FR-aminoluciferin as substrate preincubated for 15 mins before substrate addition measured after 1 hr by luminescence assay	ic50	0.0001	uM
[(2S)-3,3-dimethyl-1-[3-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]butan-2-yl] N-[(3S)-1,2-dioxo-1-(1H-pyrazol-5-ylamino)heptan-3-yl]carbamate	1797900: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2006.10.102: “Acyclic, orally bioavailable ketone-based cathepsin K inhibitors.”	ic50	0.0002	uM
tert-butyl N-[[2-[benzyl(methyl)amino]-2-oxoethyl]-cyanoamino]carbamate	1168919: Inhibition of human cathepsin S using Z-Phe-Arg-AMC fluorogenic substrate fluorogenic substrate incubated for 60 mins	ki	0.0002	uM
2-cyano-4-(cyclohexylamino)-N-[2-(3-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0002	uM
(2R)-N-(1-cyanocyclopropyl)-3-(4-pyridin-2-ylpiperazin-1-yl)sulfonyl-2-[(2-thiophen-2-ylacetyl)amino]propanamide	1675896: Inhibition of recombinant human Cathepsin S expressed in baculovirus infected insect cells using Z-VVR-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 10 mins by fluorescence assay	ki	0.0002	uM
(2R)-3-(3-bromophenyl)sulfonyl-N-(1-cyanocyclopropyl)-2-[[(1S)-2,2,2-trifluoro-1-phenylethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0002	uM
(2R)-N-(1-cyanocyclopropyl)-3-(3,4-dichlorophenyl)sulfonyl-2-[[(1S)-2,2,2-trifluoro-1-phenylethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0002	uM
(2R)-N-(1-cyanocyclopropyl)-3-(3,4-dichlorophenyl)sulfonyl-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0002	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-3-cyclohexyl-1-oxopropan-2-yl]carbamate	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-phenylurea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-benzyl-3-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-[[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-[[4-(5-thiophen-2-yl-1,2,4-oxadiazol-3-yl)phenyl]methyl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
benzyl N-[(2S)-1-[[(2S)-1-(4-hydroxyphenyl)-3-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	255215: Apparent inhibitory constant against human cathepsin S	ki	0.0003	uM
N-[(2S)-1-[[(1R)-1-cyano-2-[(2-methylphenyl)methoxy]ethyl]amino]-4,4-dimethyl-1-oxopentan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0003	uM
N-[(2S)-1-[[(1R)-2-[(2-chlorophenyl)methoxy]-1-cyanoethyl]amino]-4-methyl-1-oxopentan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0003	uM
(2R)-N-(1-cyanocyclopropyl)-2-(pyridin-3-ylamino)-3-(4-pyridin-2-ylpiperazin-1-yl)sulfonylpropanamide	1675896: Inhibition of recombinant human Cathepsin S expressed in baculovirus infected insect cells using Z-VVR-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 10 mins by fluorescence assay	ki	0.0003	uM
(2R)-N-(1-cyanocyclopropyl)-3-[(2,3-difluorophenyl)methylsulfonyl]-2-[[(1S)-2,2,2-trifluoro-1-phenylethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0003	uM
(2R)-N-(1-cyanocyclopropyl)-3-[(2,3-difluorophenyl)methylsulfonyl]-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0003	uM
(2R)-3-(4-bromophenyl)sulfonyl-N-(1-cyanocyclopropyl)-2-[[(1S)-2,2,2-trifluoro-1-phenylethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0003	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]carbamate	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0003	uM
benzyl (2S)-2-[[(2S)-1-[5-(furan-2-yl)-1,3,4-oxadiazol-2-yl]-1-oxopentan-2-yl]carbamoyl]-4-methylpentanoate	266479: Inhibition of human cathepsin S	ki	0.0003	uM
benzyl N-[(3S)-1-[[(2S)-1-[5-(furan-2-yl)-1,3,4-oxadiazol-2-yl]-1-oxohexan-2-yl]amino]-5-methyl-1,2-dioxohexan-3-yl]carbamate	321240: Inhibition of human recombinant cathepsin S	ki	0.0003	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-[4-(5-thiophen-2-yl-1,2,4-oxadiazol-3-yl)phenyl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0003	uM
N-[(2S)-1-[[(1R)-1-cyano-2-phenylmethoxyethyl]amino]-4-methyl-1-oxopentan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0003	uM
(2S,4R)-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-(cyclohexanecarbonyl)pyrrolidine-2-carboxamide	1058734: Inhibition of human cathepsin-S using Z-Val-Val-Arg-AMC as substrate up to 20 mins by fluorescence assay	ic50	0.0003	uM
N-[(1S)-1-[1-[(1R)-1-cyanopentyl]triazol-4-yl]-1-(4-methylcyclohexyl)ethyl]thiophene-3-carboxamide	717412: Inhibition of cathepsin S using FR-aminoluciferin as substrate preincubated for 15 mins before substrate addition measured after 1 hr by luminescence assay	ic50	0.0003	uM
N-[(2S)-3-(1-methylcyclohexyl)-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-1-[[(1R)-1-cyano-2-phenylmethoxyethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0004	uM
N-[(2S)-3-(1-methylcyclohexyl)-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-3-cycloheptyl-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-1-[[(1R)-2-[(2-chlorophenyl)methoxy]-1-cyanoethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0004	uM
N-[(2S)-1-[[(1R)-1-cyano-2-phenylmethoxyethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]furan-2-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0004	uM
(2R)-N-(1-cyanocyclopropyl)-3-(cyclopropylmethylsulfonyl)-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	717412: Inhibition of cathepsin S using FR-aminoluciferin as substrate preincubated for 15 mins before substrate addition measured after 1 hr by luminescence assay	ic50	0.0004	uM
(2R)-N-(1-cyanocyclopropyl)-3-(2-methylpropylsulfonyl)-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0004	uM
(2R)-N-(1-cyanocyclopropyl)-3-(4-fluorophenyl)sulfonyl-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0004	uM
(1R,2R,4R)-4-(benzenesulfonyl)-N-(1-cyanocyclopropyl)-2-[(2S,6R)-2,6-dimethylmorpholine-4-carbonyl]cyclopentane-1-carboxamide	1058734: Inhibition of human cathepsin-S using Z-Val-Val-Arg-AMC as substrate up to 20 mins by fluorescence assay	ic50	0.0004	uM
N-[(2S)-3-(1-methylcyclopentyl)-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-3-(4-methylcyclohexyl)-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0005	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	4
Cisplatin	decreases expression, decreases response to substance, increases expression	3
sodium arsenite	affects expression, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Doxorubicin	affects response to substance, decreases expression	2
Hydrogen Peroxide	decreases reaction, increases expression	2
Nickel	increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	increases expression	2
aristolochic acid I	increases expression	1
OTX015	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
potassium perchlorate	increases expression	1
glycolaldehyde	decreases activity	1
asperphenamate	affects binding, decreases activity	1
benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide	increases cleavage, increases reaction	1
potassium chromate(VI)	decreases expression	1
benazol P	affects expression	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
monomethylarsonous acid	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
thifluzamide	decreases expression	1
picoxystrobin	decreases expression	1

ChEMBL screening assays

328 unique, capped per target: 313 binding, 9 admet, 5 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4678410	Binding	Selectivity index, ratio of pKi for human cathepsin S to pKi for recombinant human cathepsin K using Z-Leu-Arg-AMC as substrate measured after 20 mins	Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L. — *Bioorg Med Chem*
CHEMBL4041063	ADMET	Inhibition of human cathepsin S expressed in Escherichia coli using Z-Val-Val-Arg-AMC as substrate by kinetic fluorescence assay	Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer’s Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides. — *J Med Chem*
CHEMBL5576503	Toxicity	Inhibition of human Cathepsin S	A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19. — *J Med Chem*

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B9XE	Abcam THP-1 CTSS KO	Cancer cell line	Male
CVCL_D7N6	Ubigene A-549 CTSS KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CTSS across ~30M SureChEMBL compounds — explore on Sugi Predict.