GZMB

Summary

GZMB (granzyme B, HGNC:4709) is a protein-coding gene on chromosome 14q12, encoding Granzyme B (P10144). Abundant protease in the cytosolic granules of cytotoxic T-cells and NK-cells which activates caspase-independent pyroptosis when delivered into the target cell through the immunological synapse.

This gene encodes a member of the granzyme subfamily of proteins, part of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) and proteolytically processed to generate the active protease, which induces target cell apoptosis. This protein also processes cytokines and degrades extracellular matrix proteins, and these roles are implicated in chronic inflammation and wound healing. Expression of this gene may be elevated in human patients with cardiac fibrosis.

Source: NCBI Gene 3002 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 54 total
• Druggable target: yes
• MANE Select transcript: NM_004131

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4709
Approved symbol	GZMB
Name	granzyme B
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	CCPI, CGL-1, CSP-B, CGL1, CTSGL1, HLP, SECT
Ensembl gene	ENSG00000100453
Ensembl biotype	protein_coding
OMIM	123910
Entrez	3002

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 nonsense_mediated_decay

ENST00000216341, ENST00000382540, ENST00000415355, ENST00000526004, ENST00000530830, ENST00000532263, ENST00000554242, ENST00000859020

RefSeq mRNA: 2 — MANE Select: NM_004131 NM_001346011, NM_004131

CCDS: CCDS86381, CCDS9633

Canonical transcript exons

ENST00000216341 — 5 exons

Exon	Start	End
ENSE00000889480	24634106	24634190
ENSE00001735218	24630954	24631214
ENSE00003574394	24632324	24632459
ENSE00003684835	24632915	24633062
ENSE00003686744	24631858	24632118

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 99.51.

FANTOM5 (CAGE): breadth broad, TPM avg 16.2045 / max 3435.1036, expressed in 257 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142642	13.0631	235
142643	2.0685	78
142644	1.0729	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.51	gold quality
blood	UBERON:0000178	95.33	gold quality
leukocyte	CL:0000738	90.45	gold quality
mononuclear cell	CL:0000842	89.63	gold quality
monocyte	CL:0000576	89.35	gold quality
spleen	UBERON:0002106	86.80	gold quality
bone marrow	UBERON:0002371	84.92	gold quality
decidua	UBERON:0002450	84.12	gold quality
lymph node	UBERON:0000029	83.76	gold quality
right lung	UBERON:0002167	82.32	gold quality
vermiform appendix	UBERON:0001154	82.09	gold quality
palpebral conjunctiva	UBERON:0001812	82.08	gold quality
upper lobe of left lung	UBERON:0008952	81.35	gold quality
bone marrow cell	CL:0002092	81.19	gold quality
periodontal ligament	UBERON:0008266	80.73	gold quality
upper lobe of lung	UBERON:0008948	79.06	gold quality
gall bladder	UBERON:0002110	77.05	gold quality
apex of heart	UBERON:0002098	76.56	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	75.99	gold quality
caecum	UBERON:0001153	74.89	gold quality
lung	UBERON:0002048	73.15	gold quality
right lobe of liver	UBERON:0001114	72.61	gold quality
omental fat pad	UBERON:0010414	71.23	gold quality
peritoneum	UBERON:0002358	71.15	gold quality
adipose tissue of abdominal region	UBERON:0007808	70.92	gold quality
superficial temporal artery	UBERON:0001614	70.78	silver quality
trabecular bone tissue	UBERON:0002483	70.57	gold quality
tonsil	UBERON:0002372	70.24	gold quality
gingiva	UBERON:0001828	69.15	silver quality
gingival epithelium	UBERON:0001949	69.06	silver quality

Single-cell (SCXA)

Detected in 46 experiment(s), a significant marker in 46.

Experiment	Marker?	Max mean expression
E-MTAB-6505	yes	35493.36
E-MTAB-8498	yes	14215.16
E-HCAD-8	yes	10119.07
E-CURD-84	yes	7095.44
E-GEOD-106540	yes	6126.56
E-CURD-126	yes	5978.17
E-GEOD-130148	yes	5958.14
E-GEOD-139324	yes	5815.13
E-MTAB-6701	yes	5806.14
E-MTAB-6653	yes	5469.04
E-MTAB-8410	yes	5295.22
E-MTAB-8322	yes	5157.32
E-MTAB-8530	yes	5069.86
E-MTAB-10432	yes	5012.35
E-HCAD-36	yes	4875.12

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, BCL6, CEBPZ, CREB1, ELF4, ESR1, ETS1, FOXP1, IKZF1, JUN, JUNB, MITF, NFKB, PRDM1, RUNX1, RUNX3, TFAP2A

miRNA regulators (miRDB)

12 targeting GZMB, 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-202-3P	99.84	71.41	1290
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-378F	98.43	65.66	554
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378C	98.43	66.10	548
HSA-MIR-378D	98.43	66.10	548
HSA-MIR-378E	98.43	65.99	551
HSA-MIR-378H	98.43	66.16	545
HSA-MIR-378I	98.43	66.10	548
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-4678	97.59	68.31	902

Literature-anchored findings (GeneRIF, showing 40)

• expressed during acute cellular rejection episodes after kidney transplantation (PMID:12009596)
• A comparison of proforms and mature forms of granzyme B in regulating granulopoiesis (PMID:12135665)
• most WT1- and proteinase 3-reactive CD8 T-cells observed in patients with acute myeloid leukemia were granzyme B(+). (PMID:12200377)
• expression of granzyme B in plasmacytoid dendritic cells (PMID:12384430)
• proapoptotic granzyme is exocytosed predominantly as a macromolecular complex with serglycin (PMID:12388539)
• Sequence analysis of this gene do not support it as a candidate gene for familial hemophagocytic lymphohistiocytosis. (PMID:12483306)
• Results suggest that cell-mediated cytotoxicity during HIV-1 infection may be impaired due to a deficient quantity of active granule proteins such as granzyme B or to their abnormal regulation. (PMID:12645627)
• granzyme B initiates caspase processing but cannot fully process procaspase-3 in intact Jurkat T leukemia or NT2 neuronal cells (PMID:12648450)
• granzyme B mediates direct cleavage of caspase 3 and also activates mitochondrial disruption, resulting in the release of proapoptotic proteins that suppress caspase inhibition (PMID:12648453)
• GrB expression is present in normal human articular chondrocytes and elevated in rheumatoid arthritis chondrocytes (PMID:12913938)
• Expressed in blood as a marker of kidney transplantation rejection. (PMID:12919092)
• Granzyme B is a caspase-like serine protease that is released by cytotoxic lymphocytes to kill virus-infected and tumor cells. (PMID:14499262)
• PMNs contain perforin and granzyme B, the 2 molecules known as the cytotoxic entity of natural killer cells and of cytotoxic T lymphocytes (PMID:14512315)
• granzyme B leakage-induced cell death is an important determinant of activation-induced NK cell death. (PMID:14635036)
• These results suggest that the main pathway of cytotoxic T lymphocyte-mediated apoptosis in peptic ulcer formation is the perforin/granzyme pathway irrespective of H. pylori infection. (PMID:14696402)
• Levels predict acute rejection in small intestine transplants. (PMID:14697980)
• serglycin-bound granzyme B in high-molecular-weight degranulate material from cytotoxic T lymphocytes predominantly followed a dynamin-dependent pathway to kill target cells (PMID:14739229)
• the RAH allele represents a neutral polymorphism in the GrB gene; it retains pro-apoptotic activity (PMID:14752093)
• expression levels of granzyme B mRNA was significantly higher in the patients undergoing acute rejection as compared to patients with stable lung function (PMID:14967307)
• examined the correlation between injury of the hepatocytes and mRNA expression of FasL and perforin/granzyme B in liver tissue to investigate the roles of both the FasL and the perforin/granzyme B pathways in chronic hepatitis B (PMID:14996347)
• Mcl-1L degradation by either GrB or caspase-3 interferes with Bim sequestration by Mcl-1L (PMID:15014070)
• granzyme H complements the pro-apoptotic function of granzyme B in human NK cells (PMID:15069086)
• results demonstrate discordant expression of granzymes A and B in human lymphocyte subsets and T regulatory cells, which suggests that different granzymes may play unique roles in immune system responses and regulation (PMID:15238416)
• proteinase inhibitor 9 was effectively hydrolyzed and inactivated by human granzyme M, raising the possibility that this orphan granzyme bypasses proteinase inhibitor 9 inhibition of granzyme B (PMID:15494398)
• cell surface heparan sulfate-bound GzmB was taken up rapidly into intracellular lysosomal compartments; blocking treatments had no an inhibitory influence on induced apoptosis (PMID:15528317)
• granzyme B targets a highly restricted range of substrates and orchestrates cellular demolition largely through activation of caspase-3 (PMID:15569669)
• Patients with disease flares were characterized by higher proportions of perforin- and/or granzyme B-positive lymphocytes with a differentiated effector phenotype (CCR7- and CD45RA+). (PMID:15641052)
• expression of proteinase inhibitor-9 and granzyme B mRNAs may be controlled through different pathways (PMID:15673968)
• Data show that granzyme B directly cleaves ROCK II, and that this causes constitutive kinase activity and bleb formation. (PMID:15699075)
• mechanism of delivery is proposed entailing electrostatic transfer of granzyme B from serglycin to cell surface proteins (PMID:15788411)
• etiologic agent of Kawasaki Disease interferes with expression of this cytotoxic protein by CD8 T lymphocytes, prolonging inflammation in the arterial wall and leading to coronary artery aneurysm formation. (PMID:15818305)
• determination of role in cell detachment in immortalized and transformed cell lines as well as normal cell lines (PMID:15843372)
• Cytotoxic T-lymphocyte precursor frequency can be determined by the granzyme B and interferon gamma marker for determining donor-specific cytolytic activity after clinical organ transplantation. (PMID:15880044)
• polymorphonuclear leukocytes from mice and humans lack the 3 cytotoxic effector molecules, granzyme A, gzmB, and perforin, generally associated with natural killer and cytotoxic T lymphocytes (PMID:15998831)
• In an electrostatic “exchange-adsorption” model, cationic sites participate in binding of GrB to the cell surface, thereby promoting its uptake and eventual release into the cytoplasm (PMID:16107729)
• Mice lacking funcitonal MST1R are suceptible to acute lung injury and have increased expression of granzymes in the lung, thymus and spleen (PMID:16166746)
• Intracellular and extracellular effects of human GrB in tumor cell lines using recombinant protein expressed in the yeast Pichia pastoris. (PMID:16336214)
• granzyme B directly attacks a major component of the cell cytoskeleton, which may contribute to the incapacitation of target cells during CTL/NK-mediated killing (PMID:16415351)
• UV-B induces GrB and PFN expression in keratinocytes, and these cells acquire acquire a significant cytotoxicity, which is GrB and PFN dependent, toward a variety of cellular targets. (PMID:16524880)
• granzyme B is released from cytolytic granules to the cytosol of CD8(+) T lymphocytes upon CD3/Receptors, Antigen, T-Cell stimulation and escapes protease inhibitor 9, thereby mediating apoptotic cell death (PMID:16547231)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gzmb	ENSMUSG00000015437
mus_musculus	Gzmf	ENSMUSG00000015441
mus_musculus	Gzmn	ENSMUSG00000015443
mus_musculus	Gzme	ENSMUSG00000022156
mus_musculus	Gzmg	ENSMUSG00000040284
mus_musculus	Gzmd	ENSMUSG00000059256
mus_musculus	Gzmc	ENSMUSG00000079186
rattus_norvegicus	Gzmf	ENSRNOG00000028810
rattus_norvegicus	Gzmn	ENSRNOG00000029860
rattus_norvegicus	Gzmbl1	ENSRNOG00000045973
rattus_norvegicus	Gzmfl1	ENSRNOG00000049919
rattus_norvegicus	Gzmbl3	ENSRNOG00000049976
rattus_norvegicus	Gzmc	ENSRNOG00000071303
rattus_norvegicus		ENSRNOG00000071306
rattus_norvegicus		ENSRNOG00000071307
rattus_norvegicus		ENSRNOG00000072988
rattus_norvegicus		ENSRNOG00000073246
rattus_norvegicus		ENSRNOG00000073731
rattus_norvegicus		ENSRNOG00000083222
rattus_norvegicus		ENSRNOG00000084027
rattus_norvegicus		ENSRNOG00000089884
rattus_norvegicus	Gzmbl3	ENSRNOG00000090964

Paralogs (6): CMA1 (ENSG00000092009), CTSG (ENSG00000100448), GZMH (ENSG00000100450), KLK6 (ENSG00000167755), KLK13 (ENSG00000167759), AZU1 (ENSG00000172232)

Protein

Protein identifiers

Granzyme B — P10144 (reviewed: P10144)

Alternative names: C11, CTLA-1, Cathepsin G-like 1, Cytotoxic T-lymphocyte proteinase 2, Fragmentin-2, Granzyme-2, Human lymphocyte protein, SECT, T-cell serine protease 1-3E

All UniProt accessions (6): P10144, E9PID1, E9PLX4, E9PRD7, J3KPK2, J3KQ52

UniProt curated annotations — full annotation on UniProt →

Function. Abundant protease in the cytosolic granules of cytotoxic T-cells and NK-cells which activates caspase-independent pyroptosis when delivered into the target cell through the immunological synapse. It cleaves after Asp. Once delivered into the target cell, acts by catalyzing cleavage of gasdermin-E (GSDME), releasing the pore-forming moiety of GSDME, thereby triggering pyroptosis and target cell death. Seems to be linked to an activation cascade of caspases (aspartate-specific cysteine proteases) responsible for apoptosis execution. Cleaves caspase-3, -9 and -10 (CASP3, CASP9 and CASP10, respectively) to give rise to active enzymes mediating apoptosis. Cleaves and activates CASP7 in response to bacterial infection, promoting plasma membrane repair.

Subcellular location. Secreted. Cytolytic granule.

Activity regulation. Inactivated by the serine protease inhibitor diisopropylfluorophosphate.

Induction. By staphylococcal enterotoxin A (SEA) in peripheral blood leukocytes.

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

RefSeq proteins (2): NP_001332940, NP_004122* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR043504

Pfam: PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.79 — granzyme B (BRENDA: 8 organisms, 289 substrates, 69 inhibitors, 38 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ACETYL-IEFD-7-AMIDO-4-METHYLCOUMARIN	0.15–1.3	5
BOC-ALA-ALA-ASP-SBZL	0.082–0.683	4
2-AMINOBENZOYL-IEPDSSMEK-DNP	0.0058–0.0387	3
ACETYL-IKPD-7-AMIDO-4-METHYLCOUMARIN	1.18–1.8	3
ABZ-IEPDSSMESK-DNP	0.0057–0.0058	2
AC-IEPD-P-NITROANILIDE	0.1512–0.447	2
ACETYL-IEPD-7-AMIDO-4-METHYLCOUMARIN	0.37–2.7	2
ACETYL-IETD-P-NITROANILIDE	6.16–7.38	2
IEPD-P-NITROANILIDE	0.027–0.067	2
LEED-P-NITROANILIDE	0.082–0.117	2
VEID-P-NITROANILIDE	0.088–0.17	2
2-AMINOBENZOYL-IEPDSSMESK-DNP	0.0058	1
2-AMINOBENZOYL-VVADSSMASK-DNP	0.0701	1
2-AMINOBENZOYL-VVADSSMESK-DNP	0.013	1
2-AMINOBENZOYL-VVAESSMESK-DNP	0.0643	1

UniProt features (40 total): strand 13, helix 4, turn 4, disulfide bond 3, sequence variant 3, sequence conflict 3, active site 3, glycosylation site 2, signal peptide 1, propeptide 1, chain 1, domain 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1IAU	X-RAY DIFFRACTION	2
1FQ3	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10144-F1	92.59	0.85

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 (4): 64 (charge relay system); 108 (charge relay system); 203 (charge relay system); 228 (mediates preference for asp-containing substrates)

Disulfide bonds (3): 49–65, 142–209, 173–188

Glycosylation sites (2): 71, 104

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2197563	NOTCH2 intracellular domain regulates transcription
R-HSA-5620971	Pyroptosis
R-HSA-75108	Activation, myristolyation of BID and translocation to mitochondria
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer

MSigDB gene sets: 358 (showing top): MODULE_172, REACTOME_SIGNALING_BY_NOTCH, MCLACHLAN_DENTAL_CARIES_UP, GOBP_INFLAMMATORY_RESPONSE, MODULE_45, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, CAGCTG_AP4_Q5, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, chr14q12, GOLDRATH_ANTIGEN_RESPONSE, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION

GO Biological Process (15): apoptotic process (GO:0006915), negative regulation of translation (GO:0017148), killing of cells of another organism (GO:0031640), natural killer cell mediated cytotoxicity (GO:0042267), obsolete proteolysis involved in protein catabolic process (GO:0051603), protein maturation (GO:0051604), pyroptotic inflammatory response (GO:0070269), granzyme-mediated programmed cell death signaling pathway (GO:0140507), positive regulation of protein localization to mitochondrion (GO:1903749), plasma membrane repair (GO:0001778), positive regulation of immune response to tumor cell (GO:0002839), proteolysis (GO:0006508), protein secretion (GO:0009306), ceramide biosynthetic process (GO:0046513), pyroptotic cell death (GO:0141201)

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

GO Cellular Component (10): immunological synapse (GO:0001772), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), cytolytic granule (GO:0044194), cytolytic granule lumen (GO:1904856), extracellular region (GO:0005576), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by NOTCH2	1
Regulated Necrosis	1
Intrinsic Pathway for Apoptosis	1
Signaling by ALK fusions and activated point mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
programmed cell death	3
protein metabolic process	2
apoptotic signaling pathway	1
execution phase of apoptosis	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
cell killing	1
disruption of cell in another organism	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
gene expression	1
inflammatory response	1
signal transduction	1
protein localization to mitochondrion	1
regulation of protein localization to mitochondrion	1
positive regulation of protein localization	1
plasma membrane organization	1
wound healing	1
immune response to tumor cell	1
positive regulation of response to tumor cell	1
regulation of immune response to tumor cell	1
positive regulation of immune response	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
pyroptotic inflammatory response	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1

Protein interactions and networks

STRING

3552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GZMB	PRF1	P14222	999
GZMB	GNLY	P09325	977
GZMB	SHC1	P29353	964
GZMB	GAB2	Q9UQC2	947
GZMB	SERPINB9	P50453	941
GZMB	IFNG	P01579	935
GZMB	CD8A	P01732	935
GZMB	CD4	P01730	921
GZMB	SRGN	P10124	921
GZMB	IL2	P01585	882
GZMB	FASLG	P48023	881
GZMB	LAG3	P18627	879
GZMB	NCAM1	P13591	856
GZMB	TNF	P01375	852
GZMB	TBX21	Q9UL17	848

IntAct

10 interactions, top by confidence:

A	B	Type	Score
GZMB	SRGN	psi-mi:“MI:0915”(physical association)	0.520
SRGN	GZMB	psi-mi:“MI:0915”(physical association)	0.520
FN1	GZMB	psi-mi:“MI:0570”(protein cleavage)	0.440
GZMB	DBP	psi-mi:“MI:0194”(cleavage reaction)	0.440
GZMB	PRF1	psi-mi:“MI:0915”(physical association)	0.400
PRF1	GZMB	psi-mi:“MI:0915”(physical association)	0.400
ELANE	GZMB	psi-mi:“MI:0915”(physical association)	0.400
GZMB	EEA1	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (32): SERPINB9 (Reconstituted Complex), SRGN (Reconstituted Complex), UBE4A (Biochemical Activity), Hspa1b (Biochemical Activity), Fgfr1 (Biochemical Activity), Notch1 (Biochemical Activity), Abl1 (Biochemical Activity), Hnrnph2 (Biochemical Activity), Pabpc1 (Biochemical Activity), Brpf1 (Biochemical Activity), Itsn1 (Biochemical Activity), LMNA (Biochemical Activity), GZMB (Affinity Capture-MS), GZMB (Affinity Capture-Western), PRKDC (Biochemical Activity)

ESM2 similar proteins: A7WPL7, O35164, O35205, O46683, O88780, P00770, P04187, P07288, P08883, P08884, P09582, P09650, P10144, P11032, P11034, P13366, P15119, P17977, P20151, P20718, P21812, P21842, P21844, P23946, P28293, P33619, P36368, P36369, P43430, P49862, P50339, P50340, P50341, P52195, P56435, P79204, P80219, P80931, P85202, P97592

Diamond homologs: A0A1S4HE51, B8VIV4, O35164, O46683, P08883, P10144, P11034, P18291, P21844, P28293, P43430, P50339, P50340, P50341, Q00356, Q28278, Q28380, Q28506, A7WPL7, O35205, O60259, O88780, P00746, P00752, P00760, P00761, P00762, P00763, P00764, P00770, P00772, P00773, P04187, P06870, P06871, P07146, P07288, P08311, P08426, P08882

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GZMB	up-regulates	IGF2R	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

603 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24631852:TCTTA:T	donor_loss	1.0000
14:24631854:TTA:T	donor_loss	1.0000
14:24631855:TA:T	donor_loss	1.0000
14:24631856:A:AG	donor_loss	1.0000
14:24632115:CCAG:C	acceptor_gain	1.0000
14:24632116:CAG:C	acceptor_gain	1.0000
14:24632116:CAGC:C	acceptor_gain	1.0000
14:24634102:TCA:T	donor_loss	1.0000
14:24634103:CA:C	donor_loss	1.0000
14:24634104:A:AC	donor_gain	1.0000
14:24634104:A:C	donor_loss	1.0000
14:24634105:C:CC	donor_gain	1.0000
14:24634105:C:CG	donor_loss	1.0000
14:24634105:CCTG:C	donor_gain	1.0000
14:24631211:CCCC:C	acceptor_gain	0.9900
14:24631212:CCC:C	acceptor_gain	0.9900
14:24631212:CCCC:C	acceptor_gain	0.9900
14:24631213:CC:C	acceptor_gain	0.9900
14:24631213:CCC:C	acceptor_gain	0.9900
14:24631214:CC:C	acceptor_gain	0.9900
14:24632114:TCCAG:T	acceptor_gain	0.9900
14:24632115:CCAGC:C	acceptor_gain	0.9900
14:24632117:AG:A	acceptor_gain	0.9900
14:24632118:GC:G	acceptor_loss	0.9900
14:24632119:C:CC	acceptor_gain	0.9900
14:24632122:G:C	acceptor_gain	0.9900
14:24632122:G:GC	acceptor_gain	0.9900
14:24632318:CCTCA:C	donor_loss	0.9900
14:24632319:CTCA:C	donor_loss	0.9900
14:24632320:TCAC:T	donor_loss	0.9900

AlphaMissense

1613 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24632017:C:A	W147C	0.986
14:24632017:C:G	W147C	0.986
14:24631107:A:C	F236L	0.981
14:24631107:A:T	F236L	0.981
14:24631109:A:G	F236L	0.981
14:24632339:G:C	D108E	0.976
14:24632339:G:T	D108E	0.976
14:24632340:T:A	D108V	0.974
14:24632340:T:G	D108A	0.974
14:24631098:C:A	W239C	0.973
14:24631098:C:G	W239C	0.973
14:24632944:G:C	F58L	0.972
14:24632944:G:T	F58L	0.972
14:24632946:A:G	F58L	0.972
14:24632962:G:C	F52L	0.970
14:24632962:G:T	F52L	0.970
14:24632964:A:G	F52L	0.970
14:24632019:A:G	W147R	0.965
14:24632019:A:T	W147R	0.965
14:24631209:G:C	D202E	0.963
14:24631209:G:T	D202E	0.963
14:24632341:C:G	D108H	0.963
14:24631895:C:G	C188S	0.958
14:24631896:A:T	C188S	0.958
14:24632936:G:A	T61I	0.958
14:24632924:C:G	C65S	0.955
14:24632925:A:T	C65S	0.955
14:24632340:T:C	D108G	0.952
14:24632923:A:C	C65W	0.951
14:24631210:T:G	D202A	0.949

dbSNP variants (sampled 300 via entrez): RS1000952534 (14:24633324 C>A,G,T), RS1000984724 (14:24632267 A>G), RS1001102790 (14:24632544 AG>A), RS1001249318 (14:24630862 G>T), RS1001575818 (14:24630518 G>A), RS1001649222 (14:24636022 C>T), RS1001986127 (14:24634609 A>G,T), RS1002015867 (14:24634916 A>G), RS1003113622 (14:24635442 G>A), RS1003514958 (14:24631739 G>A), RS1004166032 (14:24630493 G>A), RS1004180207 (14:24634295 G>A), RS1004348845 (14:24635934 A>G,T), RS1004591533 (14:24633258 A>G), RS1004804368 (14:24636160 C>T)

Disease associations

OMIM: gene MIM:123910 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000662_6	Vitiligo	3.000000e-08
GCST004785_15	Vitiligo	9.000000e-16
GCST006585_1901	Blood protein levels	3.000000e-83
GCST006585_2778	Blood protein levels	2.000000e-08
GCST008477_32	Emphysema annual change measurement in smokers (adjusted lung density)	3.000000e-06
GCST012435_2	Interleukin-10 levels in non-alcoholic fatty liver disease x mastiha supplementation interaction	4.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement
EFO:0004750	interleukin 10 measurement
EFO:0600067	mastiha supplement exposure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2316 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

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

Ligand	Action	Affinity	Parameter
compound 20 [PMID:12127536]	Inhibition	8.15	pKi

ChEMBL bioactivities

107 potent at pChembl≥5 of 107 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	Kd	0.5	nM	CHEMBL6164502
8.96	Kd	1.1	nM	CHEMBL6176523
8.96	Kd	1.1	nM	CHEMBL6176352
8.15	Ki	7	nM	CHEMBL255387
8.15	Ki	7	nM	CHEMBL71654
8.15	Ki	7	nM	CHEMBL306860
8.10	Ki	8	nM	CHEMBL428244
8.10	Ki	8	nM	CHEMBL304368
7.89	Ki	13	nM	CHEMBL71493
7.89	Ki	13	nM	CHEMBL305293
7.80	Ki	16	nM	CHEMBL303031
7.42	Ki	38	nM	CHEMBL306381
7.13	Ki	74	nM	CHEMBL303944
7.12	Ki	75	nM	CHEMBL304727
7.10	Ki	80	nM	CHEMBL70602
7.07	Ki	85	nM	CHEMBL436855
7.07	Ki	85	nM	CHEMBL69027
6.91	Ki	122	nM	CHEMBL71937
6.88	Ki	133	nM	CHEMBL69482
6.82	IC50	150	nM	CHEMBL6054518
6.82	IC50	150	nM	CHEMBL5844066
6.82	IC50	150	nM	CHEMBL5825994
6.82	IC50	150	nM	CHEMBL5884931
6.82	IC50	150	nM	CHEMBL5869326
6.82	IC50	150	nM	CHEMBL5976775
6.82	IC50	150	nM	CHEMBL5856288
6.82	IC50	150	nM	CHEMBL5764879
6.82	IC50	150	nM	CHEMBL5905868
6.82	IC50	150	nM	CHEMBL5998557
6.82	IC50	150	nM	CHEMBL5997647
6.82	IC50	150	nM	CHEMBL5742270
6.82	IC50	150	nM	CHEMBL5889501
6.82	IC50	150	nM	CHEMBL6054279
6.82	IC50	150	nM	CHEMBL5986706
6.82	IC50	150	nM	CHEMBL5836080
6.82	IC50	150	nM	CHEMBL5834015
6.82	IC50	150	nM	CHEMBL5994644
6.82	IC50	150	nM	CHEMBL6049598
6.82	IC50	150	nM	CHEMBL5806197
6.82	IC50	150	nM	CHEMBL5797804
6.82	IC50	150	nM	CHEMBL6036143
6.82	IC50	150	nM	CHEMBL5981256
6.82	IC50	150	nM	CHEMBL5939882
6.82	IC50	150	nM	CHEMBL5804054
6.82	IC50	150	nM	CHEMBL5780392
6.82	IC50	150	nM	CHEMBL5853523
6.82	IC50	150	nM	CHEMBL6010141
6.82	IC50	150	nM	CHEMBL5801983
6.82	IC50	150	nM	CHEMBL5800643
6.82	IC50	150	nM	CHEMBL5777976

PubChem BioAssay actives

21 with measured affinity, of 53 total; 21 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
(3S)-3-[[(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-4-oxo-4-(5-phenyl-1,3,4-oxadiazol-2-yl)butanoic acid	74998: Inhibition against human granzyme B	ki	0.0070	uM
(2S,11S)-11-[[(2S,3S)-2-[[2-(1-benzothiophen-3-yl)acetyl]amino]-3-methylpentanoyl]amino]-12-oxo-N-(1H-pyrazol-4-ylmethyl)-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carboxamide	74998: Inhibition against human granzyme B	ki	0.0070	uM
(3S)-3-[[(2S,11S)-11-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-4-oxo-4-(5-phenyl-1,3,4-oxadiazol-2-yl)butanoic acid	321219: Inhibition of granzyme B	ki	0.0070	uM
(2R)-2-[[(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-3-oxopropanoic acid	74998: Inhibition against human granzyme B	ki	0.0080	uM
(3S)-3-[[(2S,11S)-11-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-4-oxobutanoic acid	321219: Inhibition of granzyme B	ki	0.0080	uM
(2S,11S)-11-[[(2S,3S)-3-methyl-2-[(2-phenylacetyl)amino]pentanoyl]amino]-12-oxo-N-(1H-pyrazol-4-ylmethyl)-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carboxamide	74998: Inhibition against human granzyme B	ki	0.0130	uM
(3S)-3-[[(2S)-1-[2-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]acetyl]-2,3-dihydroindole-2-carbonyl]amino]-4-oxobutanoic acid	74998: Inhibition against human granzyme B	ki	0.0130	uM
(3S)-3-[[(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-5-methoxy-4,5-dioxopentanoic acid	74998: Inhibition against human granzyme B	ki	0.0160	uM
(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-N-(2H-triazol-4-ylmethyl)-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carboxamide	74998: Inhibition against human granzyme B	ki	0.0380	uM
(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-N-(2H-tetrazol-5-ylmethyl)-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carboxamide	74998: Inhibition against human granzyme B	ki	0.0740	uM
(2S,11S)-11-[[(2R)-3-methyl-2-pyridin-2-ylbutanoyl]amino]-12-oxo-N-(2H-triazol-4-ylmethyl)-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carboxamide	74998: Inhibition against human granzyme B	ki	0.0750	uM
(4S)-4-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-5-[(2S)-2-[[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-5-oxopentanoic acid	74998: Inhibition against human granzyme B	ki	0.0800	uM
(3S)-3-[[(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-4-(1,3-benzothiazol-2-yl)-4-oxobutanoic acid	74998: Inhibition against human granzyme B	ki	0.0850	uM
(3S)-3-[[(2S,11S)-11-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-4-(1,3-benzothiazol-2-yl)-4-oxobutanoic acid	321219: Inhibition of granzyme B	ki	0.0850	uM
(3S)-3-[[(3S,6S,8aS)-6-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carbonyl]amino]-4-oxobutanoic acid	74998: Inhibition against human granzyme B	ki	0.1220	uM
(3S)-3-[[2-[3-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-2-oxo-1-pyridinyl]acetyl]amino]-4-oxobutanoic acid	74998: Inhibition against human granzyme B	ki	0.1330	uM
(3S)-3-[[(2S)-1-[2-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoic acid	74998: Inhibition against human granzyme B	ki	0.2700	uM
(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-N-[(3-oxo-1,2-oxazol-5-yl)methyl]-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carboxamide	74998: Inhibition against human granzyme B	ki	0.3600	uM
3-[[(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]propanoic acid	74998: Inhibition against human granzyme B	ki	0.5800	uM
(3S)-3-[[(2S,11S)-11-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-5-[(4-fluorophenyl)methylsulfanyl]-4-oxopentanoic acid	74998: Inhibition against human granzyme B	ki	2.3000	uM
sodium [(2R)-3-[[(2S)-1-[[(2S,5S,8S,11R,12S,15Z,18S,21R)-2,5-dibenzyl-8-[(2R)-butan-2-yl]-15-ethylidene-21-hydroxy-4,11-dimethyl-3,6,9,13,16,22-hexaoxo-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-2-methoxy-3-oxopropyl] sulfate	732092: Inhibition of Granzyme B (unknown origin) using Ac-IEPD-AMC substrate incubated for 15 mins prior to substrate addition measured for 2 hrs	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	increases expression, affects cotreatment, decreases expression, increases abundance, decreases reaction	2
Ziram	decreases expression	2
GSK-J4	decreases expression	1
trichostatin A	decreases reaction, increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one	increases expression	1
2-(1’H-indole-3’-carbonyl)thiazole-4-carboxylic acid methyl ester	increases expression	1
(+)-JQ1 compound	decreases expression	1
walrycin A	increases expression	1
Bortezomib	increases expression	1
Zoledronic Acid	affects expression, affects reaction	1
Fulvestrant	decreases expression, increases expression	1
Vehicle Emissions	decreases reaction, increases expression	1
Azacitidine	decreases reaction, increases secretion	1
Carbamazepine	increases secretion	1
Dichlorvos	decreases expression	1
Diuron	decreases secretion, decreases reaction	1
Ethambutol	increases secretion	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Menthol	increases expression	1
Nickel	increases expression	1
Poly I-C	decreases reaction, increases expression	1
Rifampin	increases secretion	1
Tamoxifen	increases expression, decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tetradecanoylphorbol Acetate	increases expression	1
Dronabinol	increases expression	1
Tretinoin	decreases expression	1
Gold Compounds	increases expression	1

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1218388	Binding	Inhibition of granzyme B-mediated aggregation at 30 uM after 30 mins by spectrophotometry in absence of Triton X-100	Inhibition of a viral enzyme by a small-molecule dimer disruptor. — Nat Chem Biol

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8H2	Abcam HCT 116 GZMB KO	Cancer cell line	Male
CVCL_B9JC	Abcam A-549 GZMB KO	Cancer cell line	Male
CVCL_D2FG	Abcam MCF-7 GZMB KO	Cancer cell line	Female

Clinical trials (associated diseases)

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