CTSH

Summary

CTSH (cathepsin H, HGNC:2535) is a protein-coding gene on chromosome 15q25.1, encoding Pro-cathepsin H (P09668). Important for the overall degradation of proteins in lysosomes.

The protein encoded by this gene is a lysosomal cysteine proteinase important in the overall degradation of lysosomal proteins. It is composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. The encoded protein, which belongs to the peptidase C1 protein family, can act both as an aminopeptidase and as an endopeptidase. Increased expression of this gene has been correlated with malignant progression of prostate tumors. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1512 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 73 total
• Phenotypes (HPO): 30
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004390

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2535
Approved symbol	CTSH
Name	cathepsin H
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Aliases	ACC-4, ACC-5, ACC4, ACC5
Ensembl gene	ENSG00000103811
Ensembl biotype	protein_coding
OMIM	116820
Entrez	1512

Gene structure

Transcript identifiers

Ensembl transcripts: 75 — 28 retained_intron, 26 nonsense_mediated_decay, 18 protein_coding, 2 protein_coding_CDS_not_defined, 1 non_stop_decay

ENST00000220166, ENST00000525807, ENST00000527138, ENST00000527715, ENST00000528191, ENST00000528436, ENST00000528741, ENST00000529263, ENST00000529612, ENST00000529861, ENST00000530010, ENST00000530929, ENST00000533777, ENST00000534038, ENST00000534237, ENST00000534268, ENST00000534533, ENST00000615999, ENST00000649928, ENST00000676486, ENST00000676510, ENST00000676588, ENST00000676596, ENST00000676639, ENST00000676668, ENST00000676671, ENST00000676738, ENST00000676763, ENST00000676808, ENST00000676850, ENST00000676865, ENST00000676880, ENST00000677011, ENST00000677049, ENST00000677102, ENST00000677207, ENST00000677238, ENST00000677254, ENST00000677316, ENST00000677320, ENST00000677367, ENST00000677448, ENST00000677534, ENST00000677789, ENST00000677810, ENST00000677874, ENST00000677921, ENST00000677936, ENST00000678031, ENST00000678033, ENST00000678114, ENST00000678281, ENST00000678283, ENST00000678397, ENST00000678415, ENST00000678487, ENST00000678644, ENST00000678727, ENST00000678799, ENST00000678817, ENST00000678841, ENST00000678886, ENST00000678940, ENST00000679017, ENST00000679047, ENST00000679125, ENST00000679172, ENST00000679211, ENST00000679334, ENST00000906226, ENST00000906227, ENST00000906228, ENST00000906229, ENST00000969896, ENST00000969897

RefSeq mRNA: 3 — MANE Select: NM_004390 NM_001319137, NM_001411095, NM_004390

CCDS: CCDS10308, CCDS92047

Canonical transcript exons

ENST00000220166 — 12 exons

Exon	Start	End
ENSE00001866662	78921058	78922205
ENSE00003471593	78922993	78923118
ENSE00003492490	78925334	78925440
ENSE00003537664	78927713	78927781
ENSE00003567421	78934978	78935082
ENSE00003638633	78931451	78931506
ENSE00003649291	78939140	78939171
ENSE00003673862	78935680	78935750
ENSE00003683025	78937318	78937423
ENSE00003690225	78932372	78932458
ENSE00003787933	78929412	78929493
ENSE00003904144	78944891	78945046

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 81.4082 / max 1418.7102, expressed in 1601 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151138	77.9099	1581
151139	2.2465	1012
151136	0.7303	189
151137	0.3743	208
151135	0.1472	83

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cranial nerve II	UBERON:0000941	99.83	gold quality
nephron tubule	UBERON:0001231	99.45	gold quality
lower lobe of lung	UBERON:0008949	99.32	gold quality
bronchial epithelial cell	CL:0002328	99.19	gold quality
adult mammalian kidney	UBERON:0000082	99.15	gold quality
renal medulla	UBERON:0000362	99.05	gold quality
visceral pleura	UBERON:0002401	99.05	gold quality
epithelium of bronchus	UBERON:0002031	99.03	gold quality
monocyte	CL:0000576	98.95	gold quality
bronchus	UBERON:0002185	98.94	gold quality
mononuclear cell	CL:0000842	98.88	gold quality
lymph node	UBERON:0000029	98.84	gold quality
leukocyte	CL:0000738	98.83	gold quality
upper lobe of lung	UBERON:0008948	98.77	gold quality
adult organism	UBERON:0007023	98.72	gold quality
upper lobe of left lung	UBERON:0008952	98.72	gold quality
gall bladder	UBERON:0002110	98.71	gold quality
parotid gland	UBERON:0001831	98.51	gold quality
lung	UBERON:0002048	98.50	gold quality
kidney epithelium	UBERON:0004819	98.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.45	gold quality
nasal cavity epithelium	UBERON:0005384	98.41	gold quality
upper leg skin	UBERON:0004262	98.39	gold quality
vermiform appendix	UBERON:0001154	98.29	gold quality
endocervix	UBERON:0000458	98.21	gold quality
right lung	UBERON:0002167	98.07	gold quality
granulocyte	CL:0000094	97.98	gold quality
metanephros cortex	UBERON:0010533	97.94	gold quality
kidney	UBERON:0002113	97.89	gold quality
caecum	UBERON:0001153	97.69	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-HCAD-38	yes	889.35
E-MTAB-9801	yes	544.22
E-HCAD-1	yes	109.27
E-HCAD-4	yes	72.47
E-MTAB-8142	yes	41.16
E-MTAB-10553	yes	32.48
E-MTAB-5061	yes	28.38
E-GEOD-134144	yes	27.56
E-CURD-112	yes	27.45
E-HCAD-10	yes	26.78
E-CURD-122	yes	26.73
E-MTAB-9221	yes	26.26
E-GEOD-130148	yes	25.62
E-MTAB-6701	yes	24.17
E-GEOD-81547	yes	22.22

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
MMP2	Activation
MMP3	Activation

Upstream regulators (CollecTRI, top): GATA2

miRNA regulators (miRDB)

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

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-3616-3P	96.96	65.45	983
HSA-MIR-4491	96.53	66.20	935
HSA-MIR-4657	96.53	66.57	895
HSA-MIR-8081	96.42	67.75	738
HSA-MIR-627-5P	95.51	66.80	509

Literature-anchored findings (GeneRIF, showing 25)

• involvement in processing of hydrophobic surfactant-associated protein C in type II pneumocytes (PMID:12034564)
• production of cathepsins B and H by tumor cells along with concomitant decrease of their inhibitor, cystatin C, in the CSF might contribute in the process of metastasis and spread of the cancer cells in the leptomeningeal tissues (PMID:12589965)
• Cathepsin H could contribute to the transformation of LDL to an atherogenic moiety; the process might involve a self-sustaining amplifying circle. (PMID:12615673)
• kinetic data on substrates hydrolysis and enzyme inhibition show the role of the mini-chain as a framework for transition state stabilization of free alpha-amino groups of substrates and as a structural barrier for endopeptidase-like substrate cleavage. (PMID:14515996)
• AKR1B1 and CTSH may be good markers for prediction of sensitivity to certain drugs (PMID:14662023)
• cathepsin H is involved in maturation of the biologically active surfactant associated protein B (PMID:14766755)
• cathepsin H has a role in progression of colorectal cancer that is distinct from that of cathepsins B and L (PMID:15646835)
• A general defect in napsin A or cathepsin H expression or activity was not the specific cause for abnormal surfactant accumulation in juvenile pulmonary alveolar proteinosis (PMID:18216060)
• cathepsin B, cathepsin H, cathepsin X and cystatin C may have roles in inflammatory breast cancer (PMID:18949742)
• 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)
• 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)
• CTSH overexpression in a subset hepatoma may be thyroid hormone receptor dependent and suggests that this overexpression has an important role in hepatoma progression. (PMID:21217776)
• The processing of procathepsin H is an autocatalytic, multistep process proceeding from an inactive 41kDa pro-form, through a 30kDa intermediate form, to the 28kDa mature form. (PMID:22704610)
• Quantification of immunohistochemistry showed that there is no difference in the global expression of CTSD, CTSH and CTSK between asthmatics and non-asthmatics. (PMID:23483898)
• The data provide strong evidence that CTSH is an important regulator of beta-cell function during progression of T1D (PMID:24982147)
• mutation in LRPAP1 is associated with high myopia. Further studies are expected to evaluate the pathogenicity of the variants in CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2. (PMID:25525168)
• In conclusion, CTSH/rs3825932 and ERBB3/rs2292239 SNPs were associated with reduced risk of progression to proliferative diabetic retinopathy and two-step progression of diabetic retinopathy on the ETDRS scale accordingly. (PMID:26245339)
• Especially, rs3825932 in CTSH has integrative functional evidence supporting the association with type 1 diabetes mellitus. (PMID:26429317)
• p41 fragment is also shown to reduce the secretion of interleukin-12 (IL-12/p70) during the subsequent maturation of treated dendritic cells. (PMID:26960148)
• the up-regulation of MMP genes is mediated through degradation of class IIa histone deacetylases (HDACs) by certain cysteine cathepsins (Cts). (PMID:28157489)
• Study presents the crystal structures of human procathepsin H at 2.00 A and 1.66 A resolution. These structures allow us to explore in detail the molecular basis for the inhibition of the mature domain by the prodomain. Comparison with cathepsin H structure reveals how mini-chain reorients upon activation. Results demonstrate that procathepsin H is not auto-activated but can be trans-activated by cathepsin L. (PMID:30044821)
• The Rac2 GTPase contributes to cathepsin H-mediated protection against cytokine-induced apoptosis in insulin-secreting cells. (PMID:32814070)
• Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation. (PMID:33992646)
• Functional genomics identify causal variant underlying the protective CTSH locus for Alzheimer’s disease. (PMID:36739351)
• Cathepsin H: Molecular characteristics and clues to function and mechanism. (PMID:37148981)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsh	ENSDARG00000041108
mus_musculus	Ctsh	ENSMUSG00000032359
rattus_norvegicus	Ctsh	ENSRNOG00000014064
caenorhabditis_elegans		WBGENE00008861

Paralogs (12): CTSZ (ENSG00000101160), CTSC (ENSG00000109861), CTSL (ENSG00000135047), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSS (ENSG00000163131), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Protein

Protein identifiers

Pro-cathepsin H — P09668 (reviewed: P09668)

All UniProt accessions (27): A0A087X0D5, A0A0B4J217, P09668, A0A3B3IRM7, A0A7I2V2E4, A0A7I2V2L7, A0A7I2V2T8, A0A7I2V314, A0A7I2V3E8, A0A7I2V3T9, A0A7I2V439, A0A7I2V4H2, A0A7I2V4N9, A0A7I2V4W0, A0A7I2V4X5, A0A7I2V532, A0A7I2V563, A0A7I2V673, A0A7I2YQ92, A0A7I2YQE6, A0A7I2YQH4, A0A7I2YQL1, A0A7I2YQL6, A0A7I2YQX6, E9PKT6, E9PN60, E9PN84

UniProt curated annotations — full annotation on UniProt →

Function. Important for the overall degradation of proteins in lysosomes.

Subunit / interactions. Composed of a mini chain and a large chain. The large chain may be split into heavy and light chain. All chains are held together by disulfide bonds.

Subcellular location. Lysosome.

Similarity. Belongs to the peptidase C1 family.

RefSeq proteins (3): NP_001306066, NP_001398024, NP_004381* (*=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 3.4.22.16 — cathepsin H (BRENDA: 16 organisms, 94 substrates, 306 inhibitors, 41 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ARG-4-METHYLCOUMARYL-7-AMIDE	0.097–72	3
BENZOYL-DL-ARG-2-NAPHTHYLAMIDE	0.039–4.32	3
ARG-2-NAPHTHYLAMIDE	0.097–0.169	2
BENZOYL-L-PHE-L-VAL-L-ARG-4-METHYLCOUMARYL-7-AMI	0.025–0.038	2
H-L-ARG-NH-4-METHYLCOUMARYL-7-AMIDE	0.05–3.6	2
L-LEU-BETA-NAPHTHYLAMIDE	0.203–0.22	2
ALA-4-METHYLCOUMARYL-7-AMIDE	210	1
ALPHA-N-BENZOYL-DL-ARG-BETA-NAPHTHYLAMIDE	0.367	1
BENZOYL-ARG-2-NAPHTHYLAMIDE	0.637	1
BENZOYL-ARG-4-METHYLCOUMARYL-7-AMIDE	0.321	1
BENZOYL-L-ARG-2-NAPHTHYLAMIDE	0.46	1
BENZOYL-L-PHE-L-ARG-7-AMIDO-4-METHYLCOUMARIN	0.082	1
BENZYLOXYCARBONYL-PRO-ALA-ALA-ALA-PRO	7.4	1
BENZYLOXYCARBONYL-PRO-ALA-ALA-ALA-PRO-NH2	3.5	1
CITRULLINE-4-METHYLCOUMARYL-7-AMIDE	0.076	1

UniProt features (50 total): helix 14, strand 12, sequence variant 5, disulfide bond 4, chain 3, active site 3, propeptide 2, glycosylation site 2, turn 2, signal peptide 1, peptide 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6CZS	X-RAY DIFFRACTION	1.66
6CZK	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09668-F1	94.30	0.91

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): 141; 281; 301

Disulfide bonds (4): 102–327, 138–181, 172–214, 272–322

Glycosylation sites (2): 101, 230

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2132295	MHC class II antigen presentation
R-HSA-5683826	Surfactant metabolism
R-HSA-6798695	Neutrophil degranulation
R-HSA-1280218	Adaptive Immune System
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 501 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, KOBAYASHI_EGFR_SIGNALING_24HR_UP, REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, GOBP_METANEPHROS_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BASSO_B_LYMPHOCYTE_NETWORK, GOCC_SECRETORY_GRANULE, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_LUNG_MORPHOGENESIS, IVANOVA_HEMATOPOIESIS_MATURE_CELL

GO Biological Process (26): metanephros development (GO:0001656), T cell mediated cytotoxicity (GO:0001913), adaptive immune response (GO:0002250), immune response-regulating signaling pathway (GO:0002764), proteolysis (GO:0006508), immune response (GO:0006955), spermatogenesis (GO:0007283), positive regulation of gene expression (GO:0010628), positive regulation of epithelial cell migration (GO:0010634), neuropeptide catabolic process (GO:0010813), bradykinin catabolic process (GO:0010815), antigen processing and presentation (GO:0019882), positive regulation of cell migration (GO:0030335), zymogen activation (GO:0031638), protein destabilization (GO:0031648), response to retinoic acid (GO:0032526), membrane protein proteolysis (GO:0033619), surfactant homeostasis (GO:0043129), obsolete proteolysis involved in protein catabolic process (GO:0051603), dichotomous subdivision of terminal units involved in lung branching (GO:0060448), ERK1 and ERK2 cascade (GO:0070371), cellular response to thyroid hormone stimulus (GO:0097067), lysosomal protein catabolic process (GO:1905146), response to odorant (GO:1990834), positive regulation of apoptotic signaling pathway (GO:2001235), apoptotic process (GO:0006915)

GO Molecular Function (15): endopeptidase activity (GO:0004175), aminopeptidase activity (GO:0004177), cysteine-type endopeptidase activity (GO:0004197), serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), cysteine-type endopeptidase activator activity involved in apoptotic process (GO:0008656), HLA-A specific activating MHC class I receptor activity (GO:0030108), kininogen binding (GO:0030984), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), thyroid hormone binding (GO:0070324), protein binding (GO:0005515), peptidase activator activity involved in apoptotic process (GO:0016505), hydrolase activity (GO:0016787)

GO Cellular Component (15): outer dense fiber (GO:0001520), acrosomal vesicle (GO:0001669), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), lysosome (GO:0005764), cytosol (GO:0005829), axoneme (GO:0005930), extracellular matrix (GO:0031012), secretory granule lumen (GO:0034774), cytoplasmic ribonucleoprotein granule (GO:0036464), extracellular exosome (GO:0070062), alveolar lamellar body (GO:0097208), multivesicular body lumen (GO:0097486), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Immune System	2
Adaptive Immune System	1
Metabolism of proteins	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
immune system process	2
peptidase activity	2
endopeptidase activity	2
protein binding	2
binding	2
secretory granule	2
cytoplasm	2
intracellular organelle lumen	2
kidney development	1
leukocyte mediated cytotoxicity	1
T cell mediated immunity	1
immune response	1
signal transduction	1
regulation of immune response	1
protein metabolic process	1
response to stimulus	1
developmental process involved in reproduction	1
male gamete generation	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
peptide catabolic process	1
catabolic process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
protein processing	1
regulation of protein stability	1
response to lipid	1
response to oxygen-containing compound	1
proteolysis	1
multicellular organismal-level chemical homeostasis	1
epithelial tube branching involved in lung morphogenesis	1
dichotomous subdivision of an epithelial terminal unit	1
exopeptidase activity	1
cysteine-type peptidase activity	1

Protein interactions and networks

STRING

1921 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSH	CSTA	P01040	884
CTSH	CTSD	P07339	817
CTSH	LGMN	Q99538	778
CTSH	C1QTNF6	Q9BXI9	661
CTSH	CLEC16A	Q2KHT3	621
CTSH	BACH2	Q9BYV9	608
CTSH	Q5Y7H0	Q5Y7H0	584
CTSH	SH2B3	Q9UQQ2	564
CTSH	PTPN2	P17706	561
CTSH	HMSD	A8MTL9	560
CTSH	TAGAP	Q8N103	542
CTSH	SLC39A5	Q6ZMH5	532
CTSH	CSTB	P04080	531
CTSH	P3H2	Q8IVL5	526
CTSH	SFTPB	P07988	522

IntAct

90 interactions, top by confidence:

A	B	Type	Score
POC5	CETN3	psi-mi:“MI:0914”(association)	0.920
POC5	CETN3	psi-mi:“MI:0914”(association)	0.770
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
DYNC1H1	CTSH	psi-mi:“MI:0915”(physical association)	0.560
CTSH	ATN1	psi-mi:“MI:0915”(physical association)	0.560
CTSH	KLK6	psi-mi:“MI:0915”(physical association)	0.560
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
SLC25A41	NUDT19	psi-mi:“MI:0914”(association)	0.530
DNAAF19	KLK10	psi-mi:“MI:0914”(association)	0.530
CST1	CTSV	psi-mi:“MI:0914”(association)	0.530
MMRN1	CTSV	psi-mi:“MI:0914”(association)	0.530
AIRE	ALOX12B	psi-mi:“MI:0914”(association)	0.530
CTSL	CTSH	psi-mi:“MI:0914”(association)	0.530
ZIC1	CTSV	psi-mi:“MI:0914”(association)	0.530
SLCO6A1	PSMD11	psi-mi:“MI:0914”(association)	0.350

BioGRID (76): CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS), CTSH (Affinity Capture-MS)

ESM2 similar proteins: A0A068CNX1, A0A072UTP9, A0A0F7G352, A0E358, A8DS38, D3ZZ07, F4JNL3, O17473, O23791, O70370, O97397, P00786, P05167, P09668, P0DO76, P14080, P15242, P22895, P25775, P25778, P25804, P35591, P41715, P43295, P43296, P49935, P55097, P80884, Q01957, Q02765, Q10716, Q10717, Q40143, Q63088, Q6YD92, Q80UB0, Q8H166, Q8HY82, Q8RWQ9, Q8VYS0

Diamond homologs: A0A068CNX1, A0A072UTP9, A0A0F7G352, A0A1S4F2V5, A2XQE8, A5HII1, B2LSD2, F4JNL3, O35186, O45734, O46427, O60911, O65039, O65493, O70370, O97397, P00785, P00786, P04989, P05167, P06797, P07154, P07711, P09648, P09668, P0DO76, P12412, P13277, P15242, P25251, P25326, P25773, P25774, P25776, P25777, P25778, P25782, P25784, P25803, P25804

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CTSH	“down-regulates quantity by destabilization”	BGLAP	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 92 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neutrophil degranulation	12	4.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2052 predictions. Top by Δscore:

Variant	Effect	Δscore
15:78922987:GCTTA:G	donor_loss	1.0000
15:78922988:CTTA:C	donor_loss	1.0000
15:78922989:TTA:T	donor_loss	1.0000
15:78922990:TACCC:T	donor_loss	1.0000
15:78922991:AC:A	donor_gain	1.0000
15:78922991:ACCC:A	donor_loss	1.0000
15:78922992:C:A	donor_loss	1.0000
15:78922992:CC:C	donor_gain	1.0000
15:78923114:AAGTA:A	acceptor_gain	1.0000
15:78923115:AGTA:A	acceptor_gain	1.0000
15:78923116:GTA:G	acceptor_gain	1.0000
15:78923117:TA:T	acceptor_gain	1.0000
15:78923119:C:CC	acceptor_gain	1.0000
15:78925330:TCACC:T	donor_loss	1.0000
15:78925331:CACCT:C	donor_loss	1.0000
15:78925332:A:AC	donor_gain	1.0000
15:78925332:AC:A	donor_gain	1.0000
15:78925333:C:CT	donor_gain	1.0000
15:78925333:CC:C	donor_gain	1.0000
15:78925436:TCATA:T	acceptor_gain	1.0000
15:78925437:CATA:C	acceptor_gain	1.0000
15:78925437:CATAC:C	acceptor_gain	1.0000
15:78925439:TA:T	acceptor_gain	1.0000
15:78925440:AC:A	acceptor_loss	1.0000
15:78925441:C:CC	acceptor_gain	1.0000
15:78925441:C:CG	acceptor_loss	1.0000
15:78925442:T:C	acceptor_loss	1.0000
15:78925450:C:CT	acceptor_gain	1.0000
15:78925451:A:T	acceptor_gain	1.0000
15:78925456:C:CT	acceptor_gain	1.0000

AlphaMissense

2220 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:78932432:G:C	F144L	0.999
15:78932432:G:T	F144L	0.999
15:78932434:A:G	F144L	0.999
15:78932438:C:A	W142C	0.999
15:78932438:C:G	W142C	0.999
15:78932440:A:G	W142R	0.999
15:78932440:A:T	W142R	0.999
15:78922173:C:G	C322S	0.998
15:78922174:A:T	C322S	0.998
15:78922994:C:A	G311W	0.998
15:78923004:C:A	W307C	0.998
15:78923004:C:G	W307C	0.998
15:78923022:G:C	N301K	0.998
15:78923022:G:T	N301K	0.998
15:78923025:T:A	K300N	0.998
15:78923025:T:G	K300N	0.998
15:78925390:G:C	S250R	0.998
15:78925390:G:T	S250R	0.998
15:78925392:T:G	S250R	0.998
15:78931457:C:G	C181S	0.998
15:78931458:A:T	C181S	0.998
15:78932430:G:A	S145F	0.998
15:78932442:C:T	C141Y	0.998
15:78922993:C:A	G311V	0.997
15:78922993:C:T	G311E	0.997
15:78923016:C:A	W303C	0.997
15:78923016:C:G	W303C	0.997
15:78923036:A:G	W297R	0.997
15:78923036:A:T	W297R	0.997
15:78923066:C:A	G287W	0.997

dbSNP variants (sampled 300 via entrez): RS1000054384 (15:78941519 G>A), RS1000105021 (15:78941191 C>G), RS1000268396 (15:78931797 A>G), RS1000344402 (15:78926999 A>C), RS1000409180 (15:78921540 C>T), RS1000521817 (15:78926149 G>C), RS1000566526 (15:78932642 A>G), RS1000676106 (15:78930763 G>A,C), RS1000706816 (15:78928110 A>G), RS1000761720 (15:78923140 G>A), RS1000779220 (15:78927155 G>A), RS1001132690 (15:78930102 G>C), RS1001241761 (15:78936791 G>A), RS1001245743 (15:78930283 T>C,G), RS1001542877 (15:78944440 C>G,T)

Disease associations

OMIM: gene MIM:116820 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000017	Nocturia
HP:0000709	Psychosis
HP:0000711	Restlessness
HP:0000716	Depression
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000975	Hyperhidrosis
HP:0001262	Excessive daytime somnolence
HP:0001279	Syncope
HP:0001350	Slurred speech
HP:0001513	Obesity
HP:0002019	Constipation
HP:0002076	Migraine
HP:0002307	Drooling
HP:0002360	Sleep disturbance
HP:0002494	Abnormal rapid eye movement sleep
HP:0002519	Hypnagogic hallucination
HP:0002524	Cataplexy
HP:0006896	Hypnopompic hallucination
HP:0007018	Attention deficit hyperactivity disorder
HP:0007686	Abnormal pupillary function
HP:0010534	Transient global amnesia
HP:0010535	Sleep apnea
HP:0012452	Restless legs
HP:0025233	Sleep paralysis
HP:0025235	NREM parasomnia
HP:0030014	Female sexual dysfunction
HP:0040307	Male sexual dysfunction

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000258_3	Type 1 diabetes	3.000000e-15
GCST000392_4	Type 1 diabetes	8.000000e-08
GCST001164_3	Bipolar disorder	9.000000e-06
GCST005522_2	Narcolepsy	1.000000e-09
GCST005531_8	Multiple sclerosis	1.000000e-08
GCST005536_33	Type 1 diabetes	9.000000e-14
GCST006585_1101	Blood protein levels	5.000000e-166
GCST006585_1123	Blood protein levels	4.000000e-212
GCST008870_57	Keratinocyte cancer (MTAG)	2.000000e-07
GCST008871_40	Basal cell carcinoma	3.000000e-09
GCST009597_304	Multiple sclerosis	9.000000e-17
GCST009873_8	Autoimmune traits (pleiotropy)	1.000000e-14
GCST009874_34	Celiac disease	2.000000e-06
GCST009875_11	Type 1 diabetes	1.000000e-11
GCST90011899_143	Aspartate aminotransferase levels	4.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010176	keratinocyte carcinoma
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111441 (SELECTIVITY GROUP), CHEMBL2225 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 72 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL5095230	ATUZAGINSTAT	2	72

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C1: Papain

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 1b [PMID: 16290936]	Inhibition	7.4	pKi
compound 1e [PMID: 27285276]	Inhibition	6.36	pIC50

ChEMBL bioactivities

37 potent at pChembl≥5 of 46 total, top 28 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.34	Ki	0.46	nM	CHEMBL371420
8.85	Ki	1.4	nM	CHEMBL190121
7.75	IC50	18	nM	CHEMBL113948
7.40	IC50	40	nM	CHEMBL183812
7.40	IC50	40	nM	CHEMBL114161
6.96	IC50	110	nM	CHEMBL5848986
6.90	IC50	125.9	nM	CHEMBL567341
6.86	Ki	137	nM	CHEMBL514348
6.84	IC50	145	nM	CHEMBL492175
6.72	IC50	190	nM	CHEMBL203663
6.72	IC50	190	nM	E-64
6.64	IC50	230	nM	CHEMBL204605
6.25	IC50	560	nM	ATUZAGINSTAT
6.25	IC50	560	nM	CHEMBL5783659
6.24	IC50	580	nM	CHEMBL180839
6.19	IC50	645.6	nM	CHEMBL567134
5.89	Ki	1300	nM	CHEMBL4287663
5.85	Ki	1400	nM	CHEMBL486232
5.81	IC50	1550	nM	CHEMBL5870472
5.58	IC50	2653	nM	CHEMBL390474
5.43	Ki	3700	nM	CHEMBL212521
5.30	IC50	5000	nM	CHEMBL426611
5.18	IC50	6591	nM	CHEMBL230474
5.16	Ki	7000	nM	CHEMBL4292287
5.08	IC50	8300	nM	CHEMBL183660
5.04	Ki	9200	nM	LEUPEPTIN
5.01	IC50	9800	nM	CHEMBL450997
5.00	IC50	1e+04	nM	GRASSYSTATIN A

PubChem BioAssay actives

25 with measured affinity, of 180 total; 24 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)-1-cyclohexylpropan-2-yl] N-[cyano(propan-2-yl)amino]carbamate	238907: Inhibition constant against human cathepsin H using L-Arg-b-naphthalamide	ki	0.0005	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(methyl)amino]carbamate	238891: Inhibition constant against human cathepsin H using L-Arg-b-naphthalamide	ki	0.0014	uM
[(2R)-3-methyl-1-phenylbutan-2-yl] N-[(2S)-1-oxohexan-2-yl]carbamate	260672: Inhibition of recombinant human cathepsin H in a fluorescence assay	ic50	0.0180	uM
[(2S)-1-phenylpropan-2-yl] N-[(2S)-1-oxohexan-2-yl]carbamate	260672: Inhibition of recombinant human cathepsin H in a fluorescence assay	ic50	0.0400	uM
[(2S)-1-cyclohexylpropan-2-yl] 1-cyanoazetidine-2-carboxylate	242157: Inhibitory concentration against human cathepsin H using 50 uM L-Arg-beta-naphthalamide	ic50	0.0400	uM
6-(3,5-difluoroanilino)-9-ethylpurine-2-carbonitrile	444705: Inhibition of human Cathepsin H	ic50	0.1259	uM
(2S)-2-amino-N-[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]pentanamide	370548: Inhibition of human recombinant cathepsin H by fluorescence assay	ki	0.1370	uM
3-acetyl-8-chloro-2-(4-chloroanilino)-6-nitro-1H-quinolin-4-one	350739: Inhibition of human liver cathepsin H after 30 mins by fluorometric end-point assay	ic50	0.1450	uM
(2S,3S)-3-[[(2S)-1-[4-(diaminomethylideneamino)butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	360106: Inhibition of human recombinant cathepsin H after 10 mins	ic50	0.1900	uM
[(2R)-3-methyl-1-phenylbutan-2-yl] N-[(1E,2S)-1-(morpholine-4-carbonylhydrazinylidene)hexan-2-yl]carbamate	260672: Inhibition of recombinant human cathepsin H in a fluorescence assay	ic50	0.1900	uM
[(2S)-1-phenylpropan-2-yl] N-[(1E,2S)-1-(morpholine-4-carbonylhydrazinylidene)hexan-2-yl]carbamate	260672: Inhibition of recombinant human cathepsin H in a fluorescence assay	ic50	0.2300	uM
[(2S)-1-cyclohexylpropan-2-yl] 1-cyanopyrrolidine-2-carboxylate	242157: Inhibitory concentration against human cathepsin H using 50 uM L-Arg-beta-naphthalamide	ic50	0.5800	uM
9-(3,5-difluorophenyl)-6-(ethylamino)purine-2-carbonitrile	444705: Inhibition of human Cathepsin H	ic50	0.6456	uM
(2S)-1-[(2S)-2-[[(2S)-2-[[[(2S)-1-[(2S)-1-[(2S)-2-[(4-aminobenzoyl)amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]carbamoylamino]-3-phenylpropanoyl]amino]-3-hydroxypropanoyl]-N-[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(4-hydroxy-3-nitrophenyl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pyrrolidine-2-carboxamide	1402875: Reversible competitive inhibition of human cathepsin H using fluorogenic AMC-derived peptide substrate assessed as reduction in residual activity preincubated for 30 mins followed by substrate addition	ki	1.3000	uM
N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-4-methyl-1-oxopentan-2-yl]morpholine-4-carboxamide	370548: Inhibition of human recombinant cathepsin H by fluorescence assay	ki	1.4000	uM
(4S,5R)-4-(2,3-dimethylphenoxy)-6-oxa-1-azabicyclo[3.2.1]octan-7-one	290156: Inhibition of human recombinant cathepsin H	ic50	2.6530	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-(4-phenylphenyl)ethyl]butanamide	370548: Inhibition of human recombinant cathepsin H by fluorescence assay	ki	3.7000	uM
(2-methyl-2-phenylpropyl) N-[(3S)-1,2-dioxo-1-[[(1R)-1-phenylethyl]amino]heptan-3-yl]carbamate	242263: Inhibition of 50 uM L-Arg-beta-naphthalamide binding to human cathepsin H in fluorescence assay	ic50	5.0000	uM
(4S,5R)-4-phenoxy-6-oxa-1-azabicyclo[3.2.1]octan-7-one	290156: Inhibition of human recombinant cathepsin H	ic50	6.5910	uM
(4S)-4-[[(2S)-2-[[(2S)-1-[(2S)-2-[[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-acetamidoacetyl)amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoyl]amino]carbamoylamino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[[(2R)-1-[[(2R)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1402875: Reversible competitive inhibition of human cathepsin H using fluorogenic AMC-derived peptide substrate assessed as reduction in residual activity preincubated for 30 mins followed by substrate addition	ki	7.0000	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[(3S)-1-cyanopyrrolidin-3-yl]carbamate	242157: Inhibitory concentration against human cathepsin H using 50 uM L-Arg-beta-naphthalamide	ic50	8.3000	uM
(2S)-2-acetamido-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide	1125415: Inhibition of human liver cathepsin H	ki	9.2000	uM
2-amino-N-[(2S)-4-diazo-1-(4-iodophenyl)-3-oxobutan-2-yl]acetamide	360106: Inhibition of human recombinant cathepsin H after 10 mins	ic50	9.8000	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S,3R)-2-[[(3S,4S)-4-[[(2S)-4-amino-2-[[(2S)-2-[[(2R)-2-[(2S)-2-[(2S)-2-(dimethylamino)-3-methylbutanoyl]oxy-3-methylbutanoyl]oxy-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxy-6-methylheptanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	448875: Inhibition of cathepsin H after 10 to 15 mins by fluorescence assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
Estradiol	affects cotreatment, decreases expression	4
bisphenol A	affects cotreatment, increases expression, affects expression	2
sodium arsenite	decreases expression	2
Decitabine	affects cotreatment, affects expression, increases expression	2
Arsenic Trioxide	decreases expression, affects cotreatment	2
Lead	decreases expression, affects expression	2
Smoke	decreases expression	2
Cyclosporine	decreases expression	2
afuresertib	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
glycidyl methacrylate	decreases expression	1
sodium arsenate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	decreases expression	1
sodium bichromate	decreases expression	1
afimoxifene	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	affects cotreatment, increases expression	1
cupric chloride	decreases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
seocalcitol	decreases expression	1
entinostat	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	increases expression, increases secretion, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

58 unique, capped per target: 58 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL829917	Binding	Selectivity for human cathepsin H over human cathepsin K	Potent and selective ketoamide-based inhibitors of cysteine protease, cathepsin K. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2VE	Abcam HEK293T CTSH KO	Transformed cell line	Female

Clinical trials (associated diseases)

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