CTSC

Summary

CTSC (cathepsin C, HGNC:2528) is a protein-coding gene on chromosome 11q14.2, encoding Dipeptidyl peptidase 1 (P53634). Thiol protease.

This gene encodes a member of the peptidase C1 family and lysosomal cysteine proteinase that appears to be a central coordinator for activation of many serine proteinases in cells of the immune system. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate heavy and light chains that form a disulfide-linked dimer. A portion of the propeptide acts as an intramolecular chaperone for the folding and stabilization of the mature enzyme. This enzyme requires chloride ions for activity and can degrade glucagon. Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre syndrome, an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis.

Source: NCBI Gene 1075 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Papillon-Lefevre disease (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 584 total — 71 pathogenic, 16 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 34 tissues, sQTL in 14 (q < 0.05)
• Phenotypes (HPO): 47
• Drug target: yes — 1 curated mechanism-of-action drug; 3 molecules with ChEMBL bioactivity
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.05 (unconstrained)
• MANE Select transcript: NM_001814

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2528
Approved symbol	CTSC
Name	cathepsin C
Location	11q14.2
Locus type	gene with protein product
Status	Approved
Aliases	DPP1
Ensembl gene	ENSG00000109861
Ensembl biotype	protein_coding
OMIM	602365
Entrez	1075

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 26 protein_coding, 17 nonsense_mediated_decay, 4 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000227266

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 4, TSL 4: 1, TSL 5: 1

ENST00000227266, ENST00000393301, ENST00000524463, ENST00000527018, ENST00000528020, ENST00000529974, ENST00000533865, ENST00000533897, ENST00000534131, ENST00000676529, ENST00000676612, ENST00000677106, ENST00000677208, ENST00000677468, ENST00000677661, ENST00000677796, ENST00000677802, ENST00000677877, ENST00000677976, ENST00000678065, ENST00000678395, ENST00000678464, ENST00000678506, ENST00000678520, ENST00000678554, ENST00000678664, ENST00000678915, ENST00000679032, ENST00000679199, ENST00000679224, ENST00000679297, ENST00000880823, ENST00000880824, ENST00000880825, ENST00000934339, ENST00000934340, ENST00000934341, ENST00001061119, ENST00001061121, ENST00001061122, ENST00001061123, ENST00001061125, ENST00001061127, ENST00001061135, ENST00001061136, ENST00001061137, ENST00001102179, ENST00001117693, ENST00001129896, ENST00001142862

RefSeq mRNA: 3 — MANE Select: NM_001814 NM_001114173, NM_001814, NM_148170

CCDS: CCDS31654, CCDS44693, CCDS8282

Canonical transcript exons

ENST00000227266 — 7 exons

Exon	Start	End
ENSE00000743349	88296133	88296264
ENSE00000743350	88300530	88300645
ENSE00000743351	88309163	88309318
ENSE00000842724	88293592	88294508
ENSE00002140483	88337501	88337736
ENSE00003481008	88334937	88335082
ENSE00003489208	88312388	88312554

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 212.4070 / max 3516.2641, expressed in 1816 samples.

Highest expression (Bgee): palpebral conjunctiva, epithelium of nasopharynx, nasopharynx, stromal cell of endometrium, gall bladder.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CTSC is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 34 tissues and its splicing (sQTL) in 14 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 48 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	4.8e-42	+1.02	11:88341550:G:A
Whole Blood	eqtl	6.3e-31	+0.44	11:88337746:A:G
Thyroid	eqtl	3.2e-23	+0.60	11:88337746:A:G
Cells Cultured fibroblasts	eqtl	9.2e-23	-0.80	11:88410437:G:A
Whole Blood	sqtl	7.6e-10	+0.39	11:88310449:ACTAT:A
Spleen	eqtl	9.9e-10	+0.27	11:88353847:G:C
Nerve Tibial	eqtl	1.4e-08	+0.25	11:88305608:A:G
Liver	eqtl	2.1e-07	+0.57	11:88302418:T:C
Colon Sigmoid	eqtl	2.8e-07	+0.22	11:88376275:A:G
Lung	eqtl	2.9e-06	-0.34	11:88410437:G:A
Adipose Subcutaneous	eqtl	4.5e-06	+0.17	11:88342373:G:T
Adipose Visceral Omentum	eqtl	5.6e-06	+0.22	11:88349739:T:A
Thyroid	sqtl	6.0e-06	+0.51	11:88328741:C:T
Brain Frontal Cortex BA9	eqtl	7.9e-06	+0.39	11:88328741:C:T
Heart Atrial Appendage	eqtl	1.1e-05	-0.31	11:88410437:G:A
Heart Left Ventricle	eqtl	1.2e-05	+0.18	11:88417047:C:T
Artery Tibial	eqtl	1.6e-05	+0.12	11:88382416:C:T
Esophagus Muscularis	eqtl	2.9e-05	+0.16	11:88382416:C:T
Cells Cultured fibroblasts	sqtl	1.3e-04	+0.54	11:88293292:G:C
Brain Cortex	eqtl	1.3e-04	-0.54	11:87907462:A:T

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
121771	169.4225	1814
121772	23.7106	1793
121770	18.7258	1746
121773	0.4795	261
121774	0.0452	18
121775	0.0135	8
121776	0.0099	7

Top tissues by expression

showing 100 of 298 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	99.78	gold quality
epithelium of nasopharynx	UBERON:0001951	99.25	gold quality
nasopharynx	UBERON:0001728	99.24	gold quality
stromal cell of endometrium	CL:0002255	99.19	gold quality
gall bladder	UBERON:0002110	99.01	gold quality
bronchial epithelial cell	CL:0002328	98.76	gold quality
vermiform appendix	UBERON:0001154	98.76	gold quality
lymph node	UBERON:0000029	98.71	gold quality
rectum	UBERON:0001052	98.62	gold quality
monocyte	CL:0000576	98.58	gold quality
granulocyte	CL:0000094	98.53	gold quality
leukocyte	CL:0000738	98.52	gold quality
epithelium of bronchus	UBERON:0002031	98.52	gold quality
bronchus	UBERON:0002185	98.51	gold quality
mononuclear cell	CL:0000842	98.49	gold quality
caecum	UBERON:0001153	98.39	gold quality
upper lobe of left lung	UBERON:0008952	98.20	gold quality
spleen	UBERON:0002106	98.16	gold quality
upper lobe of lung	UBERON:0008948	98.16	gold quality
parotid gland	UBERON:0001831	98.02	gold quality
lung	UBERON:0002048	98.02	gold quality
decidua	UBERON:0002450	98.00	gold quality
right lung	UBERON:0002167	97.95	gold quality
eye	UBERON:0000970	97.76	gold quality
nasal cavity mucosa	UBERON:0001826	97.62	gold quality
nephron tubule	UBERON:0001231	97.61	gold quality
lower lobe of lung	UBERON:0008949	97.61	gold quality
omental fat pad	UBERON:0010414	97.49	gold quality
peritoneum	UBERON:0002358	97.48	gold quality
blood	UBERON:0000178	97.46	gold quality
placenta	UBERON:0001987	97.44	gold quality
visceral pleura	UBERON:0002401	97.36	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.30	gold quality
mammalian vulva	UBERON:0000997	97.18	gold quality
trachea	UBERON:0003126	97.07	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.01	gold quality
adult mammalian kidney	UBERON:0000082	96.98	gold quality
renal medulla	UBERON:0000362	96.95	gold quality
nasal cavity epithelium	UBERON:0005384	96.87	gold quality
penis	UBERON:0000989	96.84	gold quality
mucosa of transverse colon	UBERON:0004991	96.84	gold quality
colonic epithelium	UBERON:0000397	96.74	gold quality
gingival epithelium	UBERON:0001949	96.71	gold quality
kidney	UBERON:0002113	96.63	gold quality
ileal mucosa	UBERON:0000331	96.62	gold quality
pleura	UBERON:0000977	96.57	gold quality
germinal epithelium of ovary	UBERON:0001304	96.33	gold quality
pericardium	UBERON:0002407	96.33	gold quality
gingiva	UBERON:0001828	96.32	gold quality
pylorus	UBERON:0001166	96.31	gold quality
duodenum	UBERON:0002114	96.26	gold quality
amniotic fluid	UBERON:0000173	96.20	gold quality
oocyte	CL:0000023	96.16	gold quality
parietal pleura	UBERON:0002400	96.15	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.13	gold quality
adrenal tissue	UBERON:0018303	95.93	gold quality
smooth muscle tissue	UBERON:0001135	95.90	gold quality
colonic mucosa	UBERON:0000317	95.86	gold quality
bone marrow	UBERON:0002371	95.68	gold quality
right coronary artery	UBERON:0001625	95.54	gold quality
transverse colon	UBERON:0001157	95.50	gold quality
bone marrow cell	CL:0002092	95.48	gold quality
jejunal mucosa	UBERON:0000399	95.44	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.39	gold quality
adult organism	UBERON:0007023	95.38	gold quality
metanephros cortex	UBERON:0010533	95.34	gold quality
adipose tissue	UBERON:0001013	95.32	gold quality
metanephros	UBERON:0000081	95.31	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.30	gold quality
small intestine	UBERON:0002108	95.22	gold quality
cortex of kidney	UBERON:0001225	95.16	gold quality
coronary artery	UBERON:0001621	95.08	gold quality
kidney epithelium	UBERON:0004819	95.08	gold quality
left coronary artery	UBERON:0001626	95.03	gold quality
intestine	UBERON:0000160	94.95	gold quality
trabecular bone tissue	UBERON:0002483	94.95	gold quality
connective tissue	UBERON:0002384	94.94	gold quality
descending thoracic aorta	UBERON:0002345	94.93	gold quality
large intestine	UBERON:0000059	94.80	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.79	gold quality
tonsil	UBERON:0002372	94.76	gold quality
colon	UBERON:0001155	94.68	gold quality
endometrium	UBERON:0001295	94.66	gold quality
right adrenal gland	UBERON:0001233	94.51	gold quality
hair follicle	UBERON:0002073	94.47	gold quality
superficial temporal artery	UBERON:0001614	94.41	gold quality
left adrenal gland	UBERON:0001234	94.29	gold quality
mucosa of urinary bladder	UBERON:0001259	94.24	gold quality
synovial joint	UBERON:0002217	94.19	gold quality
adrenal gland	UBERON:0002369	94.19	gold quality
right adrenal gland cortex	UBERON:0035827	94.17	gold quality
mammary duct	UBERON:0001765	94.14	gold quality
renal glomerulus	UBERON:0000074	94.12	gold quality
left adrenal gland cortex	UBERON:0035825	94.05	gold quality
right lobe of thyroid gland	UBERON:0001119	94.02	gold quality
islet of Langerhans	UBERON:0000006	93.97	gold quality
esophagus mucosa	UBERON:0002469	93.96	gold quality
lower esophagus mucosa	UBERON:0035834	93.83	gold quality
adenohypophysis	UBERON:0002196	93.82	gold quality
oral cavity	UBERON:0000167	93.81	gold quality

Single-cell (SCXA)

Detected in 30 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-MTAB-10855	yes	3902.69
E-MTAB-10485	yes	2449.14
E-MTAB-9906	yes	2058.98
E-GEOD-114530	yes	2028.76
E-GEOD-124472	yes	1635.62
E-CURD-120	yes	1486.83
E-MTAB-7037	yes	591.52
E-HCAD-1	yes	93.30
E-CURD-122	yes	68.85
E-CURD-114	yes	61.58
E-HCAD-10	yes	60.40
E-MTAB-6701	yes	50.80
E-CURD-46	yes	41.94
E-HCAD-11	yes	41.27
E-MTAB-10287	yes	22.87

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Lung	tissue	256.9	high
Placenta	tissue	238.0	low
Lymph node	tissue	228.1	medium
Kidney	tissue	219.3	high
Spleen	tissue	185.7	medium
Rectum	tissue	179.8	medium
Appendix	tissue	174.7	low
Gallbladder	tissue	170.5	high
Urinary bladder	tissue	164.9	medium
Adipose tissue	tissue	162.0	medium
Colon	tissue	134.2	medium
Tonsil	tissue	131.8	medium
Salivary gland	tissue	123.9	medium
Small intestine	tissue	121.2	low
Duodenum	tissue	113.8	medium
Smooth muscle	tissue	83.1	low
Liver	tissue	76.7	medium
Cervix	tissue	73.1	medium
Stomach 1	tissue	69.4	medium
Bone marrow	tissue	67.7	low
Spinal cord	tissue	61.1
Breast	tissue	59.5	low
Esophagus	tissue	59.5	low
Thymus	tissue	59.5
Adrenal gland	tissue	57.3	medium
Superior colliculi	tissue	57.0
Fallopian tube	tissue	50.8	medium
Pancreas	tissue	49.2	low
Choroid plexus	tissue	45.0
Endometrium 1	tissue	41.1	medium
Vagina	tissue	40.6	not detected
Parathyroid gland	tissue	39.9	not detected
Thyroid gland	tissue	35.3	medium
Postcentral gyrus	tissue	34.9
Pituitary gland	tissue	31.9
Hippocampus	tissue	30.8	low
Nucleus accumbens	tissue	30.3
Tongue	tissue	30.0
Locus coeruleus	tissue	29.2
Olfactory bulb	tissue	28.0
Skin 1	tissue	27.9	medium
Ovary	tissue	27.4	low
Seminal vesicle	tissue	27.2	medium
Epididymis	tissue	27.0	medium
Heart muscle	tissue	24.0	low
Pons	tissue	21.5
Testis	tissue	21.3	high
Midbrain	tissue	20.5
Substantia nigra	tissue	19.8
Thalamus	tissue	19.0
Skeletal muscle	tissue	17.6	low
Prostate	tissue	16.9	not detected
Medulla oblongata	tissue	15.2
Hypothalamus	tissue	13.8
Hippocampal formation	tissue	12.3
Entorhinal cortex	tissue	12.2
Cerebral cortex	tissue	10.9	low
Retrosplenial and cingulate cortex	tissue	10.9
Insular cortex	tissue	10.8
Septum	tissue	10.5

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Blood vessel (63.7), Dorsal spinal cord (61.1), Lateral funiculus (white matter) (60.1), Anterior thalamic nucleus, ventral (58.4), Anterior funiculus (white matter) (46.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CEBPD

miRNA regulators (miRDB)

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

22 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-374C-3P	98.47	67.93	451
HSA-MIR-509-3P	98.12	67.25	612
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-5681A	97.99	67.17	1658

Functional genomics

gnomAD constraint: pLI 2.3e-08, LOEUF 1.05, missense Z -0.546 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000227266 — one region, missense o/e 1.05.

Literature-anchored findings (GeneRIF, showing 40)

• Sequencing of the mutant cathepsin C transcript revealed that it lacked exon 3, resulting in a frameshift and introduction of a premature termination codon in Papillon-Lefevre syndrome. (PMID:11914041)
• Selective inhibition prevents the partial processing of procaspase-3 in CD3-activated human CD8(+) T lymphocytes (PMID:12080079)
• Identification of a novel cathepsin C mutation (p.W185X) in a Brazilian kindred with Papillon-Lefevre syndrome. (PMID:12083812)
• All Papillon-Lefevre syndrome affected individuals from three Indian families showed three novel homozygous nonsense mutations in CTSC. (PMID:12857359)
• Three novel CTSC missense mutations found in 21 Papillon-Lefevre syndrome families, and a complete loss of CTSC function appears to be necessary for the manifestation of this phenotype. (PMID:14974080)
• homozygous deletion of 7 nucelotides in exon 4, creating a premature stop codon 11 amino acids downstream; 2 heterozygous missense mutations in exon 7: 1) substitution of leucine by arginine; 2)changing tryptophan to serine. (PMID:15111626)
• This report describes the apparent reason why the study of the natural history of human patients with Papillon-Lefevre syndrome has failed to detect a generalized T cell immunodeficiency phenotype. (PMID:15585850)
• DPP-I may play a role in converting endogenous beta-melanocortin MSH(5-22) to more potent peptides that regulate energy homeostasis in the hypothalamus. (PMID:15985311)
• The structure of the inhibitor complex provides an explanation of the substrate specificity of hDPPI, and gives a background for the design of new inhibitors. (PMID:17020538)
• inhibition of activation of multiple serine proteases with a cathepsin C inhibitor requires sustained exposure to prevent pro-enzyme processing (PMID:17535802)
• Novel mutations in two Chinese patients with Papillon-Lefevre syndrome (PMID:17652201)
• G386R missense mutation and an intragenic deletion spanning exons 3-7 and homozygous splice site mutation, p.A253SfsX30 found in papillon-Lefevre syndrome (PMID:17943190)
• study aimed to identify CTSC mutations in different Papillon-Lefevre phenotypes, including atypical forms and isolated pre-pubertal aggressive periodontitis (PMID:18294227)
• Cathepsin C propeptide interacts with intestinal alkaline phosphatase (IAP) and heat shock cognate protein 70. The propeptide of cathepsin C may stimulate the sorting to the lysosome contributing to the degradation of IAP in Caco-2 cells. (PMID:18307834)
• gene variants contribute to increased susceptibility in generalized aggressive periodontitis (PMID:18809751)
• Mutations of the cathepsin C gene are probably responsible for the phenotype of Papillon-Lefevre syndrome in this family. (PMID:18841559)
• study identified an identical recurrent missense mutation, R272P, in 3 families with Papillon-Lefevre syndrome(PLS); presence of this mutation in families from 2 different geographical areas provides evidence for founder effect for CTSC mutations in PLS (PMID:19816003)
• A novel mutation in the cathepsin C gene is reported in a Pakistani family with Papillon-Lefevre syndrome. (PMID:20236208)
• This report described a novel mutation (c.267-268del)in a family with Brazilian Papillon-Lefevre syndrome and presented a review of all cathepsin C (65) mutations reported to date. (PMID:20359428)
• Two Indian siblings present with Haim Munk syndrome (HMS) and its cardinal features including palmoplantar keratoderma, periodontitis. arachnodactyly, acroosteolysis, onychogryphosis, osteopenia as well as allelic mutation of cathepsin C exon 6 codon. (PMID:21393975)
• Processing of human protryptase in mast cells involves cathepsins L, B, and C. (PMID:21742978)
• The Cathepsin C releases the glycosidases from complexes formed with cathepsin A, and reinstates their activity. (PMID:22532132)
• present a catalytic model derived from the relative rates of the acylation vs deacylation half-reactions of cathepsin C. (PMID:22928782)
• Cathepsin C gene 5’-untranslated region mutation in papillon-lefevre syndrome in 4 unrelated families in Slovenia (PMID:23108224)
• The novel loss-of function mutation of CTSC gene (c.203 T > G) found in Papillon-Lefevre Syndrome patients correlated with their diminished enzymatic activity. (PMID:23311634)
• Report novel deletion mutation in CTSC gene in Hungarian family with Papillon-Lefevre syndrome. (PMID:23397598)
• The present account of the 148.621 kb homozygous deletion on chromosome 11 is the first report of a mutational mechanism encompassing the whole CTSC gene. (PMID:23556547)
• CTSC mutations in 5 Iranian families with Papillon-Lefevre syndrome (PLS)analyzed; modeled the protein for mutations found in 2 of them; presence of this mutation provides evidence for founder CTSC mutations in PLS; this P35delL mutation leads to loss of a leucine residue; results indicate the phenotypes in these 2 patients likely due to CTSC mutations (PMID:24374475)
• Papillon-Lefevre syndrome cause by homozygous nonsense mutation of cathepsin C gene. (PMID:24894642)
• cathepsin C in GCF does not seem to have an effect on the pathogenesis of periodontal diseases. (PMID:24949444)
• CatC has a role in the selective tuning of innate and adaptive immune responses, relevant to a chronic immune disease, such as atherosclerosis. (PMID:25395616)
• Results identify a missense mutation in CTSC gene that segregate within a family with Papillon-Lefevre syndrome. (PMID:25799584)
• Mutation screening of the CTSC gene from the two patients revealed the presence of the same homozygous nonsense mutation in Papillon-Lefevre syndrome and Haim-Munk syndromes. Phenotypic variants of the same rare disease caused by mutations of the cathepsin C (CTSC) gene. (PMID:26205983)
• A compound mutation consisting of a large deletion and a nonsense mutation, which provides a new insight in the mutation type of CTSC gene. (PMID:26385525)
• CTSC was associated with albuminuria in type 2 diabetes patients. (PMID:26631737)
• Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases. (PMID:26884336)
• Homozygous mutation 901G>A in exon 7 of CTSC gene is associated with Papillon-Lefevre syndrome. (PMID:27060303)
• CTSC gene missense mutation is responsible for Papillo- Lefevre syndrome in a Turkish family. (PMID:27062382)
• analysis of fluorescent substrates provides a detailed S’ specificity study of cathepsin C (PMID:27746119)
• expression markedly increased in the maternal vascular endothelium in subjects with preeclampsia compared with normal pregnant controls (PMID:28878298)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsc	ENSDARG00000101334
mus_musculus	Ctsc	ENSMUSG00000030560
rattus_norvegicus	Ctsc	ENSRNOG00000016496
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), CTSL (ENSG00000135047), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSS (ENSG00000163131), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:109553) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
weight loss	1
disheveled coat	1
increased thermal nociceptive threshold	1
abnormal T cell physiology	1
abnormal leukocyte migration	1
abnormal response to infection	1
sepsis	1
abnormal cytotoxic T cell physiology	1
abnormal enzyme/coenzyme activity	1
increased circulating interleukin-6 level	1
decreased circulating interleukin-6 level	1
impaired neutrophil recruitment	1
abnormal chemokine level	1
decreased prepulse inhibition	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
Pongo abelii	Q5R6D1	98.2%	Diamond
Haemonchus contortus	P19092	98.0%	Diamond
Macaca fascicularis	Q4R5M2	97.6%	Diamond
Bos taurus	P07688	94.6%	Diamond
Ovis aries	P83205	94.6%	Diamond
Sus scrofa	A1E295	91.0%	Diamond
Carica papaya	P05993	90.0%	Diamond
Canis lupus familiaris	O97578	85.0%	Diamond
Dermatophagoides pteronyssinus	P08176	84.4%	Diamond
Giardia duodenalis	P92132	82.9%	Diamond
Arabidopsis thaliana	Q93VC9	81.4%	Diamond
Gallus gallus	P43233	77.2%	Diamond
Onchocerca volvulus	Q6PN98	77.1%	Diamond
Schistosoma mansoni	P25792	75.4%	Diamond
Schistosoma japonicum	P43157	74.4%	Diamond
Ostertagia ostertagi	P25802	65.5%	Diamond
Plasmodium berghei ANKA	A0A509APV9	65.0%	Diamond
Plasmodium falciparum 3D7	Q8IIJ9	47.1%	Diamond
Dictyostelium discoideum	Q54QD9	45.8%	Diamond
Acanthamoeba polyphaga mimivirus	Q5UQE9	57.1%	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
LINC02711	ncRNA	105369423
RAB38	protein-coding	23682
GRM5	protein-coding	2915
TYR	protein-coding	7299
MIR3166	ncRNA	100423040
GRM5-AS1	ncRNA	100873989
TMEM135	protein-coding	65084
NOX4	protein-coding	50507

Protein

Protein identifiers

Dipeptidyl peptidase 1 — P53634 (reviewed: P53634)

Alternative names: Cathepsin C, Cathepsin J, Dipeptidyl peptidase I, Dipeptidyl transferase

All UniProt accessions (18): A0A7I2V2F3, A0A7I2V2Q8, A0A7I2V2V5, A0A7I2V3A2, A0A7I2V3A6, A0A7I2V3M6, A0A7I2V466, A0A7I2V4Z3, A0A7I2V592, A0A7I2V5C5, A0A7I2V5J2, A0A7I2V5L5, A0A7I2V6E3, A0A7I2YQ96, A0A7I2YQT5, P53634, H0YCY8, H0YDA2

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B.

Subunit / interactions. Tetramer of heterotrimers consisting of exclusion domain, heavy- and light chains.

Subcellular location. Lysosome.

Tissue specificity. Ubiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas.

Post-translational modifications. N-glycosylated. While glycosylation at Asn-53, Asn-119 and Asn-276 is mediated by STT3A-containing complexes, glycosylation at Asn-29 is mediated STT3B-containing complexes. In approximately 50% of the complexes the exclusion domain is cleaved at position 58 or 61. The two parts of the exclusion domain are held together by a disulfide bond.

Disease relevance. Papillon-Lefevre syndrome (PLS) [MIM:245000] An autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees. The disease is caused by variants affecting the gene represented in this entry. Haim-Munk syndrome (HMS) [MIM:245010] An autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis. The disease is caused by variants affecting the gene represented in this entry. Periodontititis, aggressive, 1 (PDON1) [MIM:170650] An autosomal recessive disease characterized by severe and protracted gingival infections, generalized or localized, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Strongly inhibited by the cysteine peptidase inhibitors mersalyl acid, iodoacetic acid and cystatin. Inhibited by N-ethylmaleimide, Gly-Phe-diazomethane, TLCK, TPCK and, at low pH, by dithiodipyridine. Not inhibited by the serine peptidase inhibitor PMSF, the aminopeptidase inhibitor bestatin, or metal ion chelators.

Cofactor. Binds 1 Cl(-) ion per heavy chain.

Induction. Up-regulated in lymphocytes by IL2/interleukin-2.

Similarity. Belongs to the peptidase C1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P53634-1	1	yes
P53634-2	2
P53634-3	3

RefSeq proteins (3): NP_001107645, NP_001805, NP_680475 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000169	Pept_cys_AS	Active_site
IPR000668	Peptidase_C1A_C	Domain
IPR013128	Peptidase_C1A	Family
IPR014882	CathepsinC_exc	Domain
IPR025660	Pept_his_AS	Active_site
IPR025661	Pept_asp_AS	Active_site
IPR036496	CathepsinC_exc_dom_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR039412	CatC	Domain

Pfam: PF00112, PF08773

Enzyme classification (BRENDA)

• EC 3.4.14.1 — dipeptidyl-peptidase I (BRENDA: 17 organisms, 142 substrates, 224 inhibitors, 37 Km, 26 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BETA-(2-THIENYL)ALA-BETA-(7-METHOXYCOUMARIN-4-YL	0.0034–0.0052	2
BETA-(2-THIENYL)ALA-BETA-(7-METHOXYCOUMARIN-4-YL	0.0022–0.0032	2
BETA-(2-THIENYL)ALA-BETA-(7-METHOXYCOUMARIN-4-YL	0.0032–0.0052	2
BETA-(2-THIENYL)ALA-PHE-7-AMIDO-4-METHYLCOUMARIN	0.003–0.0036	2
GLY-L-PHE-7-AMIDO-4-METHYLCOUMARIN	0.186–0.194	2
GLY-TRP-METHYL ESTER	0.63–1.5	2
L-SER-L-TYR-7-AMIDO-4-METHYLCOUMARIN	6.4–17	2
ALPHA-ASP-ARG-2-NAPHTHYLAMIDE	0.31	1
ASN1-ANGIOTENSIN II	0.44	1
BENZYLOXYARBONYL-GLY-L-PRO-L-ARG-7-AMIDO-4-METHY	0.028	1
BENZYLOXYCARBONYL-L-LEU-L-ARG-7-AMIDO-4-METHYLCO	0.0023	1
BENZYLOXYCARBONYL-L-PHE-L-ARG-7-AMIDO-4-METHYLCO	0.0065	1
GLUCAGON	0.027	1
GLY-ARG-2-NAPHTHYLAMIDE	0.1	1
GLY-ARG-4-METHOXY-BETA-NAPHTHYLAMIDE	0.14	1

UniProt features (100 total): sequence variant 31, strand 18, helix 14, turn 7, sequence conflict 6, disulfide bond 5, glycosylation site 4, splice variant 4, chain 3, binding site 3, active site 3, signal peptide 1, propeptide 1

Structure

Experimental structures (PDB)

18 structures by resolution:

PDB	Title	Method	Resolution (Å)
4OEL	Crystal structure of Cathepsin C in complex with dipeptide substrates	X-RAY DIFFRACTION	1.4
4OEM	Crystal structure of Cathepsin C in complex with dipeptide substrates	X-RAY DIFFRACTION	1.52
6RNI	DPP1 in complex with inhibitor	X-RAY DIFFRACTION	1.54
6RNE	DPP1 in complex with inhibitor	X-RAY DIFFRACTION	1.65
6RN7	DPP1 in complex with inhibitor	X-RAY DIFFRACTION	1.66
3PDF	Discovery of Novel Cyanamide-Based Inhibitors of Cathepsin C	X-RAY DIFFRACTION	1.85
6IC6	Human cathepsin-C in complex with cyclopropyl peptidyl nitrile inhibitor 1	X-RAY DIFFRACTION	1.9
6RN9	DPP1 in complex with inhibitor	X-RAY DIFFRACTION	1.9
2DJF	Crystal Structure of human dipeptidyl peptidase I (Cathepsin C) in complex with the …	X-RAY DIFFRACTION	2
6IC5	Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 2	X-RAY DIFFRACTION	2
6IC7	Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 3	X-RAY DIFFRACTION	2
2DJG	Re-determination of the native structure of human dipeptidyl peptidase I (cathepsin C)	X-RAY DIFFRACTION	2.05
1K3B	Crystal Structure of Human Dipeptidyl Peptidase I (Cathepsin C): Exclusion Domain Added …	X-RAY DIFFRACTION	2.15
4CDF	Human DPP1 in complex with (2S,4S)-N-((1S)-1-cyano-2-(4-(4- …	X-RAY DIFFRACTION	2.2
4CDD	Human DPP1 in complex with (2S)-N-((1S)-1-cyano-2-(4-(4-cyanophenyl) …	X-RAY DIFFRACTION	2.35
4CDC	Human DPP1 in complex with (2S)-2-amino-N-((1S)-1-cyano-2-(4- …	X-RAY DIFFRACTION	2.4
4CDE	Human DPP1 in complex with 4-amino-N-((1S)-1-cyano-2-(4-(4- …	X-RAY DIFFRACTION	2.4
6RN6	DPP1 in complex with inhibitor	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53634-F1	90.64	0.80

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Metabolic proteins, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital malformations, Congenital malformations of skin

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH enhanced · IF supported

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
258
405
427

Ligand- & substrate-binding residues (3)

Position	Role
347	chloride
302	chloride
304	chloride

Disulfide bonds (5)

Type	Positions
Disulfide bond	30–118, 54–136, 255–298, 291–331, 321–337

Glycosylation sites (4)

Type	Positions
N-linked (glcnac…) asparagine	29, 53, 119, 276

Function

Pathways and Gene Ontology

Reactome pathways

5 curated (TAS) of 15; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

15 pathways:

ID	Pathway	Evidence
R-HSA-204005	COPII-mediated vesicle transport	curated
R-HSA-5694530	Cargo concentration in the ER	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-1280218	Adaptive Immune System	—
R-HSA-446203	Asparagine N-linked glycosylation	—
R-HSA-199977	ER to Golgi Anterograde Transport	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-199991	Membrane Trafficking	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-948021	Transport to the Golgi and subsequent modification	—
R-HSA-5653656	Vesicle-mediated transport	—

MSigDB gene sets: 594 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, MODULE_172, GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_52, WALLACE_PROSTATE_CANCER_RACE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, MCLACHLAN_DENTAL_CARIES_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, MODULE_151, MODULE_45

GO Biological Process (5): T cell mediated cytotoxicity (GO:0001913), proteolysis (GO:0006508), immune response (GO:0006955), apoptotic process (GO:0006915), positive regulation of protein catabolic process (GO:0045732)

GO Molecular Function (12): cysteine-type endopeptidase activity (GO:0004197), serine-type endopeptidase activity (GO:0004252), cysteine-type peptidase activity (GO:0008234), dipeptidyl-peptidase activity (GO:0008239), peptidase activator activity involved in apoptotic process (GO:0016505), phosphatase binding (GO:0019902), chloride ion binding (GO:0031404), identical protein binding (GO:0042802), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (10): extracellular region (GO:0005576), lysosome (GO:0005764), endoplasmic reticulum lumen (GO:0005788), membrane (GO:0016020), COPII-coated ER to Golgi transport vesicle (GO:0030134), extracellular matrix (GO:0031012), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

11 top-level categories:

Category	Pathways
ER to Golgi Anterograde Transport	2
Immune System	2
Adaptive Immune System	1
Innate Immune System	1
Affinity selection of immunoglobulins	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Post-translational protein modification	1
Metabolism of proteins	1
Asparagine N-linked glycosylation	1

GO top-level categories

39 GO namespaces:

Category	Terms
cellular anatomical structure	3
endopeptidase activity	2
protein binding	2
leukocyte mediated cytotoxicity	1
T cell mediated immunity	1
protein metabolic process	1
immune system process	1
response to stimulus	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
cysteine-type peptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
exopeptidase activity	1
apoptotic process	1
peptidase activator activity	1
enzyme binding	1
anion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
lytic vacuole	1
endoplasmic reticulum	1
intracellular organelle lumen	1
coated vesicle	1
external encapsulating structure	1
endoplasmic reticulum-Golgi intermediate compartment	1
bounding membrane of organelle	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
extracellular vesicle	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 30 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
proteolysis	BP	direct assay
extracellular exosome	CC	high-throughput assay
extracellular matrix	CC	high-throughput assay
membrane	CC	high-throughput assay
cysteine-type peptidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,678 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSC	GZMA	P12544	772
CTSC	GLT6D1	Q7Z4J2	739
CTSC	CMA1	P23946	733
CTSC	CTSG	P08311	701
CTSC	GZMB	P10144	690
CTSC	PRTN3	P15637	679
CTSC	CTSD	P07339	657
CTSC	TPSAB1	P15157	641
CTSC	LGMN	Q99538	638
CTSC	ELANE	P08246	633
CTSC	SPINK5	Q9NQ38	625
CTSC	DPP7	Q9UHL4	624
CTSC	ING1	Q9UK53	620
CTSC	DSG1	Q02413	605
CTSC	KRT9	P35527	601

IntAct

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

6 partners by confidence:

Partner	Interaction type	MIscore	Records
DMWD	physical association	0.560	3
SPRED1	physical association	0.560	3
WFDC9	association	0.530	1
CST7	physical association	0.400	2
ESPN	association	0.350	2
TBC1D16	association	0.350	1

BioGRID (71 interactions; top human partners by supporting records): FBXO6 (Affinity Capture-MS; 2 records), G3BP1 (Affinity Capture-MS; 2 records), NHLRC2 (Affinity Capture-MS; 2 records), RAF1 (Affinity Capture-MS; 2 records), WFDC9 (Affinity Capture-MS; 2 records), ADSL (Co-fractionation), ANKMY2 (Co-fractionation), ARIH1 (Co-fractionation), ARMC9 (Co-fractionation), CAPN1 (Two-hybrid), CCR1 (Affinity Capture-MS), CD81 (Co-fractionation), CLIC1 (Affinity Capture-MS), CST3 (Affinity Capture-MS), CST6 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for CTSC: 584 ClinVar records (87 pathogenic / likely pathogenic); 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	71
Likely pathogenic	16
Uncertain significance	188
Likely benign	209
Benign	37

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 87 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
7289	NM_001814.6(CTSC):c.628C>T (p.Arg210Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
139655	NM_001814.6(CTSC):c.96T>G (p.Tyr32Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
523939	NM_001814.6(CTSC):c.1141del (p.Leu381fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2925492	NM_001814.6(CTSC):c.415G>A (p.Gly139Arg)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1075099	NM_001814.6(CTSC):c.-55C>A	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2137220	NM_001814.6(CTSC):c.319-1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2167619	NM_001814.6(CTSC):c.566_572del (p.Thr189fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
575092	NM_001814.6(CTSC):c.855dup (p.Gln286fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2577359	NM_001814.6(CTSC):c.1280A>C (p.Asn427Thr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2921889	NM_001814.6(CTSC):c.757+1G>T	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
3574106	NM_001814.6(CTSC):c.1339G>T (p.Glu447Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
7301	NM_001814.6(CTSC):c.1040A>G (p.Tyr347Cys)	Pathogenic	criteria provided, single submitter	3
7292	NM_001814.6(CTSC):c.856C>T (p.Gln286Ter)	Pathogenic	criteria provided, single submitter	2
7293	NM_001814.6(CTSC):c.1047del (p.Gly350fs)	Pathogenic	criteria provided, single submitter	2
690367	NM_001814.6(CTSC):c.861_863delinsTTGGGCTTAGCCCAA (p.Glu287_Val288delinsAspTrpAlaTer)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CTSC’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 887):

Position(s)	Effect	Δscore	Sites
11:88312391	donor_gain	1.0000
11:88334935–88334936	donor_loss	1.0000	5
11:88335083	acceptor_gain	1.0000
11:88335083–88335084	acceptor_loss	1.0000	4
11:88294509–88294510	acceptor_loss	0.9900	6
11:88312555–88312556	acceptor_loss	0.9900	5
11:88337499–88337500	donor_loss	0.9900	6
11:88312383	donor_loss	0.9800	3
11:88312386–88312387	donor_loss	0.9800	6
11:88312555	acceptor_loss	0.9800

AlphaMissense

846 missense substitutions predicted likely pathogenic (of 3,055 scored), across 214 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
H405	8	0.972	0.989
N427	8	0.958	0.993
S284	8	0.901	0.997
D313	8	0.852	0.951
D379	8	0.846	0.924
F261	8	0.833	0.978
F92	8	0.832	0.978
F380	8	0.814	0.953
C255	7	0.970	0.983
W429	7	0.962	0.988
W39	7	0.961	0.992
W185	7	0.960	0.988
W423	7	0.955	0.991
C298	7	0.952	0.976
W433	7	0.949	0.981
C30	7	0.943	0.975
C291	7	0.938	0.963
S428	7	0.936	0.993
F137	7	0.934	0.984
C258	7	0.934	0.991

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Bladder Urothelial Carcinoma (TCGA)	unfavorable	1.04e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	6.04e-05

Disease associations

OMIM: gene MIM:602365 | disease phenotypes: MIM:245000, MIM:245010, MIM:170650

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
Papillon-Lefevre disease	Definitive	Autosomal recessive	3
Haim-Munk syndrome	Definitive	Autosomal recessive	5
ectodermal dysplasia syndrome	Strong	Autosomal recessive
periodontitis, aggressive 1	Limited	Unknown

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 11 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
COVID-19 research	green
Hypotonic infant	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Paediatric disorders	green
Palmoplantar keratoderma and erythrokeratodermas	green
Palmoplantar keratodermas	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Skeletal dysplasia	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (6): Papillon-Lefevre disease (MONDO:0009490), Haim-Munk syndrome (MONDO:0009491), periodontitis, aggressive (MONDO:0980757), CTSC-related disorder (MONDO:0800465), periodontitis, aggressive 1 (MONDO:0008226), ectodermal dysplasia syndrome (MONDO:0019287)

Orphanet (2): Haim-Munk syndrome (Orphanet:2342), Papillon-Lefèvre syndrome (Orphanet:678)

HPO phenotypes

47 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000166	Severe periodontitis
HP:0000230	Gingivitis
HP:0000670	Carious teeth
HP:0000704	Periodontitis
HP:0000958	Dry skin
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0000998	Hypertrichosis
HP:0001053	Hypopigmented skin patches
HP:0001073	Cigarette-paper scars
HP:0001166	Arachnodactyly
HP:0001231	Abnormal fingernail morphology
HP:0001288	Gait disturbance
HP:0001581	Recurrent skin infections
HP:0001597	Abnormal nail morphology
HP:0001763	Pes planus
HP:0001803	Nail pits
HP:0001805	Onychogryphosis
HP:0001870	Acroosteolysis of distal phalanges (feet)
HP:0002205	Recurrent respiratory infections
HP:0002230	Generalized hirsutism
HP:0002231	Sparse body hair
HP:0002514	Cerebral calcification
HP:0002797	Osteolysis
HP:0002860	Squamous cell carcinoma
HP:0002861	Melanoma
HP:0005406	Recurrent bacterial skin infections
HP:0005830	Flexion contracture of toe
HP:0006224	Tapering pointed ends of distal finger phalanges
HP:0006308	Atrophy of alveolar ridges
HP:0006323	Premature loss of primary teeth
HP:0006480	Spontaneous tooth loss
HP:0006960	Choroid plexus calcification
HP:0007545	Congenital palmoplantar hyperkeratosis
HP:0008069	Neoplasm of the skin
HP:0008404	Nail dystrophy
HP:0009771	Osteolytic defects of the phalanges of the hand
HP:0009804	Tooth agenesis
HP:0011132	Chronic furunculosis
HP:0012785	Flexion contracture of finger
HP:0030816	Gingival recession
HP:0100523	Liver abscess
HP:0100838	Recurrent cutaneous abscess formation
HP:0200039	Pustule
HP:0410027	Alveolar bone loss around teeth

GWAS associations

5 associations:

Study	Trait	p-value
GCST006585_843	Blood protein levels	2e-107
GCST008478_57	Neurological blood protein biomarker levels	3e-25
GCST008478_56	Neurological blood protein biomarker levels	3e-19
GCST008478_18	Neurological blood protein biomarker levels	5e-19
GCST90002380_88	Basophil percentage of white cells	2e-10

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007992	basophil percentage of leukocytes

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D010520	Aggressive Periodontitis	C07.465.714.533.161
D004476	Ectodermal Dysplasia	C16.131.077.350; C16.131.831.350; C16.320.850.250; C17.800.804.350; C17.800.827.250
D010214	Papillon-Lefevre Disease	C16.320.850.475.600; C17.800.428.435.600; C17.800.827.475.600
C537627	Keratosis palmoplantaris with periodontopathia and onychogryposis *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2252 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CTSC 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
BRENSOCATIB	Small molecule	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 18,215 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

3 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3353410	OSIMERTINIB	4	9,448
CHEMBL3900409	BRENSOCATIB	3	460
CHEMBL31965	CANERTINIB	3	8,307

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 (5 total), top 5:

Ligand	Action	Affinity	Parameter
GSK2793660	Inhibition	9.37	pIC50
brensocatib	Inhibition	8.4	pIC50
IcatCXPZ-01	Inhibition	7.82	pIC50
HSK31858	Inhibition	7.68	pIC50
compound 3d [PMID: 3941405]	Inhibition	5.57	pKi

Binding affinities (BindingDB)

1313 measured of 1650 human assays (1662 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[[4-[3-(3-fluorophenoxy)propylamino]-1,3,5-triazin-2-yl]amino]-N-methylbenzamide	IC50	0.13 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[3-(1-methylazetidin-3-yl)-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.18 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-2-oxospiro[1H-indole-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.2 nM	US-9540373: Substituted spirocycles
N-methyl-3-[[4-[3-(3-phenylphenoxy)azetidin-1-yl]-1,3,5-triazin-2-yl]amino]benzamide	IC50	0.24 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
CHEMBL3936580	IC50	0.251 nM
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(2-oxospiro[1H-indole-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.3 nM	US-9540373: Substituted spirocycles
(S)-2-amino-N-((S)-1-cyano-2-(5-phenylthiophen-2-yl)ethyl)-3-(thiophen-2-yl)propanamide	IC50	0.3 nM
N ((S)-1-cyano-2-(3-fluoro-4′-(pentafluoro-16-sulfanyl)-[1,1′-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide	IC50	0.3 nM	US-11807635: Nitrile derivative that acts as inhibitor of dipeptidyl peptidase 1 and use thereof
3-[[4-(4-benzyl-1,4-diazepan-1-yl)-1,3,5-triazin-2-yl]amino]-N-methylbenzamide	IC50	0.31 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[1’-(oxetan-3-yl)-1-oxospiro[2-benzofuran-3,4’-piperidine]-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.32 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
5-[[4-[3-(4-fluorophenoxy)azetidin-1-yl]-1,3,5-triazin-2-yl]amino]-N,2-dimethylbenzamide	IC50	0.37 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
CHEMBL4561264	IC50	0.398 nM
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-methyl-2-oxospiro[indole-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.4 nM	US-9540373: Substituted spirocycles
(6S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide	IC50	0.45 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxospiro[2-benzofuran-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxospiro[2-benzofuran-3,3’-pyrrolidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-1-oxospiro[2-benzofuran-3,3’-azetidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methylspiro[1,2-dihydroindene-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(2-oxospiro[1H-indole-3,3’-pyrrolidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(S) N ((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl) ethyl)-1,4-oxazepane-2-carboxamide	IC50	0.5 nM	US-11807635: Nitrile derivative that acts as inhibitor of dipeptidyl peptidase 1 and use thereof
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[3-(1-methylazetidin-3-yl)-2-oxo-1,3-benzothiazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.58 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-(2-fluoro-4-spiro[1,2-dihydroindene-3,4’-piperidine]-5-ylphenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-(1,1’-dimethyl-2-oxospiro[indole-3,4’-piperidine]-5-yl)-2-fluorophenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-1-oxospiro[2-benzofuran-3,3’-pyrrolidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-(2-fluoro-4-spiro[1H-2-benzofuran-3,4’-piperidine]-5-ylphenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.6 nM	US-9540373: Substituted spirocycles
(S) N ((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide	IC50	0.64 nM	US-20240150335: FUSED RING DERIVATIVES CONTAINING 1,4-OXAZEPANE
3-[[4-[2-(4-chlorophenoxy)ethylamino]-1,3,5-triazin-2-yl]amino]-N-methylbenzamide	IC50	0.69 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-1-oxospiro[2-benzofuran-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.7 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxospiro[2-benzofuran-3,3’-azetidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.7 nM	US-9540373: Substituted spirocycles
(S)-2-amino-N-((S)-2-(benzo[d]thiazol-2-yl)-1-cyanoethyl)-3-(thiophen-2-yl)propanamide	IC50	0.7 nM
(6S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxo-3H-2-benzofuran-5-yl)phenyl]ethyl]-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide	IC50	0.72 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(2S)-N-[(1R)-1-cyano-2-[2-fluoro-4-(1-piperidin-4-ylindazol-6-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.76 nM	US-20240150335: FUSED RING DERIVATIVES CONTAINING 1,4-OXAZEPANE
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[1’-(oxetan-3-yl)spiro[1H-2-benzofuran-3,3’-azetidine]-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.79 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
CHEMBL3261927	IC50	0.794 nM
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[5-(4-methylpiperazine-1-carbonyl)thiophen-3-yl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.8 nM	US-8987249: Substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of Cathepsin C
3-[[4-[3-(2-fluorophenoxy)azetidin-1-yl]-1,3,5-triazin-2-yl]amino]-N-methylbenzamide	IC50	0.83 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
N-methyl-3-[[4-(3-methyl-3-phenoxyazetidin-1-yl)-1,3,5-triazin-2-yl]amino]benzamide	IC50	0.84 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
N-methyl-3-[[4-[4-(3-propyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-1,3,5-triazin-2-yl]amino]benzamide	IC50	0.87 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
(1R,3S,4S)-N-[(1S)-1-cyano-2-[5-(1-oxo-3H-2-benzofuran-5-yl)thiophen-2-yl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	KI	0.9 nM	US-8871783: Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-[5-(6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carbonyl)thiophen-3-yl]-2-fluorophenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.9 nM	US-8987249: Substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of Cathepsin C
(1R,3S,4S)-N-[1-cyano-2-(3-cyano-9-fluoro-6-oxo-10bH-phenanthridin-8-yl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.9 nM	US-8987249: Substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of Cathepsin C
(S)-2-amino-N-((S)-1-cyano-2-phenylethyl)-3-(thiophen-2-yl)propanamide	IC50	0.9 nM
N-methyl-3-[[4-[(3-phenyl-1,2,4-oxadiazol-5-yl)methylamino]-1,3,5-triazin-2-yl]amino]benzamide	IC50	0.93 nM	US-12522593: Azacycloalkyl carbonyl cyclic amine compound
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[5-(4-propan-2-ylpiperazine-1-carbonyl)thiophen-3-yl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1 nM	US-8987249: Substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of Cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methylspiro[1H-2-benzofuran-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-3-oxospiro[furo[3,4-c]pyridine-1,4’-piperidine]-6-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1 nM	US-9540373: Substituted spirocycles
cis-4-(2,3-dimethylphenoxy)-6-oxa-1-aza-bicyclo[3.2.1]octan-7-one	IC50	1 nM
(S)-2-amino-N-((S)-1-cyano-2-(naphthalen-2-yl)ethyl)-3-(thiophen-2-yl)propanamide	IC50	1 nM
CHEMBL4525977	IC50	1 nM
CHEMBL5269225	IC50	1 nM

ChEMBL bioactivities

2174 potent at pChembl≥5 of 2180 total, top 49 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	CHEMBL5764453
9.60	IC50	0.2512	nM	CHEMBL3936580
9.52	IC50	0.3	nM	CHEMBL5897422
9.52	IC50	0.3	nM	CHEMBL1079888
9.40	IC50	0.3981	nM	CHEMBL4561264
9.40	IC50	0.4	nM	CHEMBL5988711
9.30	IC50	0.5	nM	CHEMBL5821570
9.30	IC50	0.5	nM	CHEMBL5993798
9.30	IC50	0.5	nM	CHEMBL6038478
9.30	IC50	0.5	nM	CHEMBL5842574
9.30	IC50	0.5	nM	CHEMBL5873696
9.22	IC50	0.6	nM	CHEMBL3662670
9.22	IC50	0.6	nM	CHEMBL5959899
9.22	IC50	0.6	nM	CHEMBL5842308
9.22	IC50	0.6	nM	CHEMBL5973708
9.22	IC50	0.6	nM	CHEMBL5847896
9.15	IC50	0.7	nM	CHEMBL3662518
9.15	IC50	0.7	nM	CHEMBL5978060
9.15	IC50	0.7	nM	CHEMBL5759659
9.15	IC50	0.7	nM	CHEMBL1081695
9.10	IC50	0.7943	nM	CHEMBL3261927
9.10	IC50	0.7943	nM	CHEMBL3261926
9.10	IC50	0.8	nM	CHEMBL3662669
9.10	IC50	0.8	nM	CHEMBL3667275
9.10	IC50	0.8	nM	CHEMBL3667371
9.10	IC50	0.8	nM	CHEMBL3667372
9.05	Ki	0.9	nM	CHEMBL3657578
9.05	IC50	0.9	nM	CHEMBL3662671
9.05	IC50	0.9	nM	CHEMBL3667276
9.05	IC50	0.9	nM	CHEMBL3667341
9.05	IC50	0.9	nM	CHEMBL1080780
9.00	IC50	1	nM	CHEMBL3261926
9.00	IC50	1	nM	CHEMBL3261920
9.00	IC50	1	nM	CHEMBL3667277
9.00	IC50	1	nM	CHEMBL3667328
9.00	IC50	1	nM	CHEMBL3667373
9.00	IC50	1	nM	CHEMBL3667394
9.00	IC50	1	nM	CHEMBL4525977
9.00	IC50	1	nM	CHEMBL450997
9.00	IC50	1	nM	CHEMBL5269225
9.00	IC50	1	nM	CHEMBL6009899
9.00	IC50	1	nM	CHEMBL5781403
9.00	IC50	1	nM	CHEMBL1081694
8.96	IC50	1.1	nM	CHEMBL5942494
8.92	IC50	1.2	nM	CHEMBL3667274
8.89	IC50	1.3	nM	CHEMBL3667342
8.89	IC50	1.3	nM	CHEMBL3667374
8.89	IC50	1.3	nM	CHEMBL3667387
8.89	IC50	1.3	nM	CHEMBL3667390

PubChem BioAssay actives

539 with measured affinity, of 943 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
(2S)-2-amino-N-[(1S)-1-cyano-2-(5-phenylthiophen-2-yl)ethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0003	uM
4-amino-N-[(1S)-1-cyano-2-[4-(1-methyl-2-oxo-3H-indol-6-yl)phenyl]ethyl]oxane-4-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0003	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-4-methylsulfanylpyrrolidine-2-carboxamide	1511299: Inhibition of recombinant human DPPI using H-Gly-Arg-AFC as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence plate reader analysis	ic50	0.0004	uM
2,5-dibromo-N-[(3R)-1-cyanopyrrolidin-3-yl]benzenesulfonamide	570622: Inhibition of human recombinant cathepsin C after 1 hr	ic50	0.0004	uM
(2S)-2-amino-N-[(1S)-2-(1,3-benzothiazol-2-yl)-1-cyanoethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0007	uM
4-amino-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]oxane-4-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0008	uM
4-amino-N-[(1S)-1-cyano-2-[4-(3-methylsulfonylphenyl)phenyl]ethyl]oxane-4-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0008	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-phenylethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0009	uM
2-amino-N-[(2S)-4-diazo-1-(4-iodophenyl)-3-oxobutan-2-yl]acetamide	1932757: Inhibition of human Cathepsin C using Ala-4-[ 125 I]Phe-DMK as substrate preincubated for 30 mins followed by substrate addition measured after 6 to 24 hrs	ic50	0.0010	uM
N-[5-[[6-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]-3-piperidin-1-yl-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0010	uM
N-[(E,3S)-6-(2,3-dihydroindol-1-yl)-6-oxohex-4-en-3-yl]-4-methyloxane-4-carboxamide	1932761: Inhibition of Cathepsin C (unknown origin)	ic50	0.0010	uM
(2S)-N-[(1S)-1-cyano-2-[4-(4-cyano-3-methylsulfanylphenyl)phenyl]ethyl]piperidine-2-carboxamide	1138553: Inhibition of cathepsin C in human THP1 cells assessed as inhibition of H-Gly-Phe-AFC cleavage by fluorescence assay	ic50	0.0010	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-naphthalen-2-ylethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0010	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-4-fluoropyrrolidine-2-carboxamide	1511299: Inhibition of recombinant human DPPI using H-Gly-Arg-AFC as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence plate reader analysis	ic50	0.0016	uM
(2S,4R)-N-[(1S)-1-cyano-2-phenylethyl]-4-methylsulfanyl-4-phenylpyrrolidine-2-carboxamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0017	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-piperidin-1-yl-2-pyridinyl]oxy]-2-(trifluoromethyl)phenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0018	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-piperidin-1-yl-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0019	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-(4-phenylphenyl)ethyl]butanamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0020	uM
2,5-dibromo-N-[(3R,5S)-1-cyano-5-methylpyrrolidin-3-yl]benzenesulfonamide	570622: Inhibition of human recombinant cathepsin C after 1 hr	ic50	0.0020	uM
4-amino-N-[(1S)-1-cyano-2-(4-phenylphenyl)ethyl]oxane-4-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0020	uM
(2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320489: Reversible inhibition of human recombinant DPP1 by surface plasmon resonance direct binding assay	kd	0.0025	uM
1-amino-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]cyclohexane-1-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0025	uM
(2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzothiazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0025	uM
N-[2-methyl-5-[[6-[4-(4-methylpiperazin-1-yl)anilino]-3-piperidin-1-yl-2-pyridinyl]oxy]phenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0027	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-(4-methylpiperazin-1-yl)-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0028	uM
(2S)-2-amino-N-[(1S)-1-cyano-2,2-diphenylethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0038	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-morpholin-4-yl-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0039	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-pyrrolidin-1-yl-2-pyridinyl]oxy]-2-(trifluoromethyl)phenyl]prop-2-enamide	1599510: Inhibition of CatL-activated recombinant human C-terminal His10-tagged cathepsin C (25 to 463 residues) expressed in mouse myeloma cells using Gly-Phe-AFC as substrate preincubated for 3 hrs followed by substrate addition and measured after 60 mins	ic50	0.0040	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(2-methyl-1-oxo-3H-isoindol-5-yl)phenyl]ethyl]-4-hydroxypiperidine-2-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0040	uM
(2S,3aS,7aS)-N-[(1S)-1-cyano-2-[4-(3-methylsulfonylphenyl)phenyl]ethyl]-2,3,3a,4,5,6,7,7a-octahydro-1H-indole-2-carboxamide	1754932: Inhibition of human cathepsin C	ic50	0.0046	uM
N-[5-[[3-(3-hydroxypiperidin-1-yl)-6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0049	uM
(2S)-N-[(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0050	uM
4-amino-N-[(1S)-1-cyano-2-[4-(2-methyl-3-oxo-1H-isoindol-5-yl)phenyl]ethyl]oxane-4-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0050	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-4-hydroxypiperidine-2-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0050	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-cyclohexylethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0051	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-(1H-indol-3-yl)ethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0058	uM
(2S)-N-[(1S)-1-cyano-2-[4-[3-(2,2-difluoroethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0063	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-4-hydroxypyrrolidine-2-carboxamide	1511299: Inhibition of recombinant human DPPI using H-Gly-Arg-AFC as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence plate reader analysis	ic50	0.0063	uM
N-[5-[[6-[[2-methoxy-6-(4-methylpiperazin-1-yl)-3-pyridinyl]amino]-3-piperidin-1-yl-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0065	uM
(2S,3aS,7aS)-N-[(1S)-1-cyano-2-[4-(3-cyano-4-methylsulfonylphenyl)phenyl]ethyl]-2,3,3a,4,5,6,7,7a-octahydro-1H-indole-2-carboxamide	1754932: Inhibition of human cathepsin C	ic50	0.0065	uM
(2S)-N-[(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320454: Inhibition of DPP1 in human U937 cells using Gly-Phe-AFC as substrate preincubated for 60 mins followed by substrate addition by fluorescence assay	ic50	0.0079	uM
3-bromo-N-[(3R)-1-cyanopyrrolidin-3-yl]benzenesulfonamide	570622: Inhibition of human recombinant cathepsin C after 1 hr	ic50	0.0079	uM
(2S)-N-[(1S)-1-cyano-2-[4-(2-methyl-1-oxo-3H-isoindol-5-yl)phenyl]ethyl]piperidine-2-carboxamide	1138553: Inhibition of cathepsin C in human THP1 cells assessed as inhibition of H-Gly-Phe-AFC cleavage by fluorescence assay	ic50	0.0079	uM
(2S,4R)-N-[(1S)-1-cyano-2-phenylethyl]-4-fluoro-4-phenylpyrrolidine-2-carboxamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0082	uM
(2S,3aS,6aS)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[b]pyrrole-2-carboxamide	1754932: Inhibition of human cathepsin C	ic50	0.0093	uM
(2S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]piperidine-2-carboxamide	1138553: Inhibition of cathepsin C in human THP1 cells assessed as inhibition of H-Gly-Phe-AFC cleavage by fluorescence assay	ic50	0.0100	uM
N-[(3R)-1-cyanopyrrolidin-3-yl]-2,5-dimethoxybenzenesulfonamide	570622: Inhibition of human recombinant cathepsin C after 1 hr	ic50	0.0100	uM
(3S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-2-azaspiro[4.4]nonane-3-carboxamide	1754932: Inhibition of human cathepsin C	ic50	0.0102	uM
(2S)-2-amino-N-[(1S)-1-cyano-3-phenylpropyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0110	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148176: Binding affinity to human CTSC incubated for 45 mins by Kinobead based pull down assay	kd	0.0113	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	6
sodium arsenite	increases abundance, increases expression, decreases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
nickel sulfate	decreases expression	4
Tetrachlorodibenzodioxin	decreases expression, increases expression	4
bisphenol A	increases expression, affects cotreatment, affects expression	3
trichostatin A	affects cotreatment, increases expression	3
Cadmium Chloride	decreases expression, increases expression	3
cobaltous chloride	decreases expression	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cisplatin	decreases expression, increases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, decreases methylation	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	increases abundance, increases expression	1
sulindac sulfide	decreases expression	1
toosendanin	increases phosphorylation, increases reaction, decreases expression, decreases reaction	1
ciglitazone	affects binding, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
pentabromodiphenyl ether	decreases expression	1
adefovir dipivoxil	decreases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
lipopolysaccharide, E coli O55-B5	decreases expression	1

ChEMBL screening assays

107 unique, capped per target: 106 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004868	Binding	Inhibition of human recombinant cathepsin C after 10 mins	Inhibition of the activation of multiple serine proteases with a cathepsin C inhibitor requires sustained exposure to prevent pro-enzyme processing. — *J Biol Chem*
CHEMBL4041066	ADMET	Inhibition of Cathepsin C (unknown origin) at 10 uM	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*

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1PL	Abcam HeLa CTSC KO	Cancer cell line	Female
CVCL_D8JL	Ubigene HCT 116 CTSC KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

19 trials:

NCT	Phase	Status	Title
NCT01116934	Not specified	COMPLETED	Cytokines in Papillon-Lefèvre Syndrome
NCT01459302	Not specified	WITHDRAWN	Genetic Study of Familial and Sporadic ALS/Motor Neuron Disease, Miyoshi Myopathy and Other Neuromuscular Disorders
NCT05271435	Not specified	COMPLETED	Digital Tools for Assessment of Motor Functions and Falls in ALS
NCT05966038	Not specified	RECRUITING	ALS/MND Natural History Study Data Repository
NCT06408727	Not specified	TEMPORARILY_NOT_AVAILABLE	Intermediate Expanded Access Protocol CNMAu8.EAP04
NCT07823101	Not specified	RECRUITING	Imaging Assessment of Swallowing and Speech Muscles in Inclusion Body Myositis
NCT00001211	Not specified	COMPLETED	Clinical Study of Oral Endosseous Titanium Implants in Edentulous Subjects
NCT00266513	Not specified	TERMINATED	Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States
NCT01108770	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia
NCT02896387	Not specified	TERMINATED	Ability of a Molecule (Prima) to Restore Physiological Differentiation in Epithelium Expressing Gene p63
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
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
NCT07468019	Not specified	RECRUITING	Organization’s Unique Protocol ID
NCT03340012	Not specified	UNKNOWN	Clinical and Radiographic Evaluation of Guided Tissue Regeneration With Radiation-sterilized Allogenic Bone Grafts or Xenogenic Grafts for the Treatment of Intrabony Defects in Aggressive Periodontitis
NCT04264624	Not specified	COMPLETED	Efficacy of Sub-gingival Air-polishing With Erythritol in the Treatment of Periodontitis
NCT05108727	Not specified	COMPLETED	Diode Laser With Periodontal Flap Surgery in Periodontitis
NCT05112471	Not specified	COMPLETED	Efficacy of GBT vs SRP+US, in the Treatment of Severe Generalized Periodontitis.
NCT07526883	Not specified	COMPLETED	The Effect of Non-Surgical Periodontal Treatment on Systemic Inflammatory Markers and Lipid Profile in Young Adults With Severe Periodontitis

Predicted chemistry — Sugi Predict

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