GZMA

Summary

GZMA (granzyme A, HGNC:4708) is a protein-coding gene on chromosome 5q11.2, encoding Granzyme A (P12544). 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.

Cytolytic T lymphocytes (CTL) and natural killer (NK) cells share the remarkable ability to recognize, bind, and lyse specific target cells. They are thought to protect their host by lysing cells bearing on their surface ’nonself’ antigens, usually peptides or proteins resulting from infection by intracellular pathogens. The protein described here is a T cell- and natural killer cell-specific serine protease that may function as a common component necessary for lysis of target cells by cytotoxic T lymphocytes and natural killer cells.

Source: NCBI Gene 3001 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 42 total
• Druggable target: yes
• MANE Select transcript: NM_006144

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4708
Approved symbol	GZMA
Name	granzyme A
Location	5q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000145649
Ensembl biotype	protein_coding
OMIM	140050
Entrez	3001

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000274306

RefSeq mRNA: 1 — MANE Select: NM_006144 NM_006144

CCDS: CCDS3965

Canonical transcript exons

ENST00000274306 — 5 exons

Exon	Start	End
ENSE00000971463	55105474	55105618
ENSE00000971464	55107794	55107935
ENSE00000971465	55108125	55108394
ENSE00001127864	55110021	55110252
ENSE00001127870	55102646	55102752

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 99.41.

FANTOM5 (CAGE): breadth broad, TPM avg 10.7202 / max 1846.3930, expressed in 194 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56460	10.7202	194

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.41	gold quality
blood	UBERON:0000178	93.25	gold quality
spleen	UBERON:0002106	92.34	gold quality
jejunal mucosa	UBERON:0000399	90.96	gold quality
lymph node	UBERON:0000029	90.83	gold quality
mucosa of transverse colon	UBERON:0004991	88.84	gold quality
duodenum	UBERON:0002114	88.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.11	gold quality
palpebral conjunctiva	UBERON:0001812	88.00	gold quality
rectum	UBERON:0001052	87.09	gold quality
gall bladder	UBERON:0002110	84.94	gold quality
decidua	UBERON:0002450	84.94	gold quality
bone marrow	UBERON:0002371	84.59	gold quality
vermiform appendix	UBERON:0001154	84.24	gold quality
endometrium	UBERON:0001295	83.46	gold quality
epithelium of nasopharynx	UBERON:0001951	82.93	gold quality
nasopharynx	UBERON:0001728	82.92	gold quality
leukocyte	CL:0000738	80.09	gold quality
germinal epithelium of ovary	UBERON:0001304	79.50	gold quality
caecum	UBERON:0001153	78.69	gold quality
trabecular bone tissue	UBERON:0002483	78.66	gold quality
periodontal ligament	UBERON:0008266	78.63	silver quality
mononuclear cell	CL:0000842	78.27	gold quality
parietal pleura	UBERON:0002400	78.16	gold quality
ileal mucosa	UBERON:0000331	78.12	gold quality
bone marrow cell	CL:0002092	77.80	gold quality
colonic mucosa	UBERON:0000317	77.76	gold quality
upper lobe of left lung	UBERON:0008952	77.74	gold quality
monocyte	CL:0000576	77.63	gold quality
pleura	UBERON:0000977	77.22	gold quality

Single-cell (SCXA)

Detected in 50 experiment(s), a significant marker in 42.

Experiment	Marker?	Max mean expression
E-MTAB-6653	yes	10144.45
E-MTAB-8410	yes	7032.22
E-GEOD-139324	yes	6932.42
E-CURD-122	yes	6763.30
E-MTAB-6701	yes	5751.19
E-HCAD-24	yes	5658.45
E-GEOD-149689	yes	3100.45
E-MTAB-9906	yes	2850.27
E-MTAB-10287	yes	2623.50
E-MTAB-7407	yes	2377.34
E-GEOD-70580	yes	2372.42
E-CURD-55	yes	2313.06
E-HCAD-36	yes	2301.55
E-CURD-120	yes	2241.80
E-GEOD-134144	yes	2178.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF5, NR3C1, TP53, VDR

Literature-anchored findings (GeneRIF, showing 40)

• HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. (PMID:11909973)
• 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)
• polymorphonuclear leukocytes from mice and humans lack the 3 cytotoxic effector molecules, gzmA, granzyme B, and perforin, generally associated with natural killer and cytotoxic T lymphocytes (PMID:15998831)
• Ku70 has other antiapoptotic functions in Granzyme A (GzmA)-induced cell death, which are blocked when GzmA proteolyses Ku70 (PMID:16440001)
• Mouse granzyme B is 30 times less cytotoxic than human granzyme B and does not require Bid for killing but regains cytotoxicity on engineering of its active site cleft. Mouse granzyme A is considerably more cytotoxic than human granzyme A. (PMID:17116752)
• GrA expression is increased in type II pneumocytes of patients with very severe COPD. These results indicate that GrA may be important in the development of COPD. (PMID:17138956)
• GzmK-induced caspase-independent death occurs through Bid-dependent mitochondrial damage that is different from GzmA (PMID:17308307)
• Report activation of the granzymeA/B pathway in children with severe respiratory syncytial virus infection. (PMID:18317234)
• GzmA accesses the mitochondrial matrix to cleave the complex I protein NDUFS3, an iron-sulfur subunit of the NADH:ubiquinone oxidoreductase complex I. (PMID:18485875)
• GZMA causes detachment of alveolar epithelial A549 cells accompanied by interleukin-8 release. (PMID:18776661)
• the granule secretory pathway plays an unexpected role in inflammation, with GzmA acting as an endogenous modulator (PMID:18951048)
• Data suggest that 1, 25(OH)(2) vitamin D(3) suppresses granzyme A probably by down-regulating Th1 cytokine response, and tah vitamin D receptor gene variants might regulate cytotoxic T-cell response by suppression of granzyme A expression in tuberculosis. (PMID:19014932)
• GrK not only constitutes a redundant functional backup mechanism that assists GrA-induced cell death but that it also displays a unique function by cleaving its own specific substrates. (PMID:19059912)
• The N-terminal GzmA cleavage fragment of PARP-1 acts as a PARP-1 dominant negative, binding to DNA and blocking DNA repair. (PMID:19506301)
• Granzyme A is a proinflammatory protease. (PMID:19875524)
• investigation of substrate specificity toward Jurkat cell proteins; more than 260 cleavage sites, almost exclusively favoring basic residues at the P1 position, in approximately 200 unique protein substrates, were identified (PMID:20536382)
• Human eosinophils exert TNF-alpha and granzyme A-mediated tumoricidal activity toward colon carcinoma cells. (PMID:21068403)
• The results indicate that GzmA and GzmB are implicated in mechanisms of neurodegeneration in amyotrophic lateral sclerosis. (PMID:21349256)
• A critical and previously unsuspected role is revealed for granzymes A and B in dictating immunogenicity by influencing the mode of tumor cell death. (PMID:21709155)
• Patients with chronic immune thrombocytopenia have elevated serum granzyme A levels. (PMID:22476618)
• functional divergence between human and mouse granzyme A (PMID:24505135)
• Serum concentrations of granzyme A in patients with ovarian cancer were substantially increased in comparison to concentrations in patients with ovarian cystadenomas or ovarian teratomas. (PMID:24673566)
• Data indicate N-terminomics on the human and mouse granzymes A and K by combined fractional diagonal chromatography (COFRADIC). (PMID:25383893)
• The exocytosed granzyme A enters target cells and mediates IL-1beta maturation independently of caspase-1 and without inducing cytotoxicity. (PMID:25437548)
• GzmA and GzmB expressing cells in the airways and lung parenchyma was higher in subjects who died from asthma (PMID:25745046)
• Carbamate pesticides significantly reduced the intracellular levels of perforin, GrA, GrB, Gr3/K, and GRN in NK-92CI cells. (PMID:25921628)
• We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model. (PMID:25928296)
• GZMA, GBP5 and CD64 genes show promise as a rapid diagnostic markers separating tuberculosis from other pulmonary diseases. (PMID:26025597)
• Taken together, the authors verified that histone H3 is a real substrate for GzmA in vivo in the Raji cells treated by staurosporin. (PMID:26032366)
• Our results suggest that granzyme A could be considered another biomarker of TB, that can be used, other than IFN-gamma, to discriminate between patients with active TB and LTBI subjects (PMID:26051682)
• Results reveal enhanced intra- and extracellular expression of gzmA and B in patients with pulmonary TB, suggesting that gzms are part of the host response to tuberculosis. (PMID:26156785)
• Levels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarker(high) patients. (PMID:26522261)
• Delivered into parasite infected cells by granulysin and perforin, granzymes generate superoxide and inactivate oxidative defense enzymes to kill the parasite. (PMID:26752517)
• GzmA plays an unfavorable role in host defense during pneumococcal pneumonia by a mechanism that does not depend on natural killer cells. (PMID:27343190)
• GzmA produced by lesional CD8 T cells has the capacity to specifically increase chemokine secretion from inflamed keratinocytes, thereby sustaining the focal inflammation in psoriasis lesions by amplifying a chemotactic inflammatory loop. (PMID:28094457)
• granzyme A in human platelets increases with aging (PMID:29167233)
• Granzyme A in Chikungunya and Other Arboviral Infections. (PMID:31993061)
• this study demonstrated that GZMA from cytotoxic lymphocytes cleaves and activates GSDMB to induce target cell pyroptosis. (PMID:32299851)
• COVID-19 pneumonia: CD8(+) T and NK cells are decreased in number but compensatory increased in cytotoxic potential. (PMID:32574709)
• Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation. (PMID:32640217)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gzma	ENSMUSG00000023132
rattus_norvegicus	Gzma	ENSRNOG00000010603
drosophila_melanogaster	CG14780	FBGN0025383
drosophila_melanogaster	CG14227	FBGN0031058
drosophila_melanogaster	CG11664	FBGN0040341
drosophila_melanogaster	CG30287	FBGN0050287
drosophila_melanogaster	CG30288	FBGN0050288
drosophila_melanogaster	CG30289	FBGN0050289
drosophila_melanogaster	CG30414	FBGN0050414
drosophila_melanogaster	CG31205	FBGN0051205
drosophila_melanogaster	CG33225	FBGN0053225
drosophila_melanogaster	CG33226	FBGN0069056
drosophila_melanogaster	CG30283	FBGN0260477

Paralogs (5): HGF (ENSG00000019991), PIK3IP1 (ENSG00000100100), GZMK (ENSG00000113088), HABP2 (ENSG00000148702), MST1 (ENSG00000173531)

Protein

Protein identifiers

Granzyme A — P12544 (reviewed: P12544)

Alternative names: CTL tryptase, Cytotoxic T-lymphocyte proteinase 1, Fragmentin-1, Granzyme-1, Hanukkah factor

All UniProt accessions (1): P12544

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 Lys or Arg. Once delivered into the target cell, acts by catalyzing cleavage of gasdermin-B (GSDMB), releasing the pore-forming moiety of GSDMB, thereby triggering pyroptosis and target cell death. Cleaves APEX1 after ‘Lys-31’ and destroys its oxidative repair activity. Cleaves the nucleosome assembly protein SET after ‘Lys-189’, which disrupts its nucleosome assembly activity and allows the SET complex to translocate into the nucleus to nick and degrade the DNA.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with APEX1.

Subcellular location. Secreted. Cytoplasmic granule.

Induction. Dexamethasone (DEX) induces expression of isoform beta and represses expression of isoform alpha. The alteration in expression is mediated by binding of glucocorticoid receptor to independent promoters adjacent to the alternative first exons of isoform alpha and isoform beta.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P12544-1	alpha	yes
P12544-2	beta

RefSeq proteins (1): NP_006135* (*=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 3.4.21.78 — granzyme A (BRENDA: 7 organisms, 52 substrates, 39 inhibitors, 11 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-ARG THIOBENZYL ESTER	0.12–0.315	2
BENZYLOXYCARBONYL-GLY-ARG THIOBENZYL ESTER	0.105–0.16	2
BENZYLOXYCARBONYL-LYS THIOBENZYL ESTER	0.13–0.19	2
BOC-ALA-ALA-ARG-SBZL	0.887	1
BOC-TRP-ARG-SBZL	0.17	1
TERT-BUTYLOXYCARBONYL-ALA-ALA-ARG THIOBENZYL EST	0.14	1
Z-ARG-SBZL	0.177	1
Z-LYS-SBZL	0.767	1
BENZYLOXYCARBONYL-LYS-THIOBENZYL ESTER	—	0

UniProt features (43 total): strand 17, sequence conflict 6, disulfide bond 4, active site 3, splice variant 2, turn 2, helix 2, signal peptide 1, propeptide 1, sequence variant 1, mutagenesis site 1, chain 1, domain 1, glycosylation site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1ORF	X-RAY DIFFRACTION	2.4
1OP8	X-RAY DIFFRACTION	2.5
9K1S	X-RAY DIFFRACTION	2.69

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12544-F1	91.60	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 (3): 69 (charge relay system); 114 (charge relay system); 212 (charge relay system)

Disulfide bonds (4): 179–197, 208–234, 54–70, 148–218

Glycosylation sites (1): 170

Mutagenesis-validated functional residues (1):

Position	Phenotype
212	abolished protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 304 (showing top): MODULE_172, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_INFLAMMATORY_RESPONSE, MODULE_45, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, WIELAND_UP_BY_HBV_INFECTION, GNF2_ZAP70, GOLDRATH_ANTIGEN_RESPONSE, MODULE_331, MODULE_75, GOBP_PROTEIN_MATURATION, FINAK_BREAST_CANCER_SDPP_SIGNATURE, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN

GO Biological Process (14): apoptotic process (GO:0006915), immune response (GO:0006955), response to bacterium (GO:0009617), killing of cells of another organism (GO:0031640), obsolete negative regulation of endodeoxyribonuclease activity (GO:0032078), positive regulation of apoptotic process (GO:0043065), negative regulation of DNA binding (GO:0043392), negative regulation of oxidoreductase activity (GO:0051354), 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), cytotoxic T cell pyroptotic cell death (GO:1902483), proteolysis (GO:0006508)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (6): immunological synapse (GO:0001772), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), cytolytic granule (GO:0044194), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
programmed cell death	2
protein metabolic process	2
apoptotic signaling pathway	1
execution phase of apoptosis	1
immune system process	1
response to stimulus	1
response to other organism	1
cell killing	1
disruption of cell in another organism	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
DNA binding	1
negative regulation of binding	1
regulation of DNA binding	1
oxidoreductase activity	1
negative regulation of catalytic activity	1
regulation of oxidoreductase activity	1
gene expression	1
inflammatory response	1
signal transduction	1
pyroptotic cell death	1
endopeptidase activity	1
serine-type peptidase activity	1
identical protein binding	1
protein dimerization activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
plasma membrane	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
lysosome	1

Protein interactions and networks

STRING

2616 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GZMA	PRF1	P14222	991
GZMA	GNLY	P09325	893
GZMA	NME1	P15531	863
GZMA	APEX1	P27695	842
GZMA	ANP32A	P39687	841
GZMA	CTSC	P53634	837
GZMA	CD8A	P01732	834
GZMA	SET	Q01105	826
GZMA	FASLG	P48023	774
GZMA	PDCD1	Q15116	746
GZMA	CXCR6	O00574	741
GZMA	CXCL9	Q07325	740
GZMA	IL2	P01585	732
GZMA	KLRB1	Q12918	728
GZMA	CD3D	P04234	726

IntAct

5 interactions, top by confidence:

A	B	Type	Score
NDUFS3	GZMA	psi-mi:“MI:0570”(protein cleavage)	0.440
GZMA	GZMA	psi-mi:“MI:0195”(covalent binding)	0.440
GZMA	HSP90AA1	psi-mi:“MI:0914”(association)	0.350
GZMA	purL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): GZMA (Reconstituted Complex), HMGB2 (Reconstituted Complex), NDUFS3 (Biochemical Activity), Ndufs3 (Biochemical Activity), LMNA (Biochemical Activity), HIST1H1A (Biochemical Activity), HIST2H2BE (Biochemical Activity), SET (Biochemical Activity), GZMA (Reconstituted Complex), ACTG1 (Biochemical Activity), HNRNPK (Biochemical Activity), HDC (Biochemical Activity), GOLGA2 (Biochemical Activity), XRCC6 (Biochemical Activity), GZMA (Affinity Capture-Western)

ESM2 similar proteins: O35164, O35205, P00752, P00755, P00756, P00770, P04071, P04187, P07628, P07647, P08882, P08883, P08884, P09582, P09650, P11032, P11033, P11034, P12544, P13366, P15119, P15946, P15948, P15949, P18291, P21812, P21844, P36368, P36369, P36373, P36374, P36375, P36376, P43430, P49863, P49864, P50339, P50340, P50341, P85202

Diamond homologs: A7WPL7, O35164, O35205, O46683, O60259, O88780, P00746, P00752, P00760, P00761, P00762, P00763, P00764, P00770, P00772, P00773, P04187, P06870, P06871, P07146, P07288, P08311, P08426, P08882, P08883, P08884, P09582, P09650, P10144, P11032, P11033, P11034, P12323, P12544, P12788, P13366, P15119, P16049, P17977, P18291

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GZMA	down-regulates	SET	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

291 predictions. Top by Δscore:

Variant	Effect	Δscore
5:55105616:CTT:C	donor_gain	1.0000
5:55105619:G:GG	donor_gain	1.0000
5:55108123:A:AG	acceptor_gain	1.0000
5:55108123:AGCT:A	acceptor_gain	1.0000
5:55108124:G:GG	acceptor_gain	1.0000
5:55108124:GCT:G	acceptor_gain	1.0000
5:55108124:GCTG:G	acceptor_gain	1.0000
5:55102749:GAAG:G	donor_gain	0.9900
5:55102751:AGG:A	donor_loss	0.9900
5:55102752:GGTAA:G	donor_loss	0.9900
5:55102753:GTAA:G	donor_loss	0.9900
5:55102754:T:G	donor_loss	0.9900
5:55105468:GAACA:G	acceptor_loss	0.9900
5:55105469:AACAG:A	acceptor_loss	0.9900
5:55105470:ACAG:A	acceptor_loss	0.9900
5:55105471:CAG:C	acceptor_loss	0.9900
5:55105472:A:AG	acceptor_gain	0.9900
5:55105472:A:G	acceptor_loss	0.9900
5:55105473:G:GG	acceptor_gain	0.9900
5:55105473:GAT:G	acceptor_gain	0.9900
5:55105615:ACTT:A	donor_gain	0.9900
5:55105615:ACTTG:A	donor_loss	0.9900
5:55105616:CTTGT:C	donor_loss	0.9900
5:55105617:TT:T	donor_gain	0.9900
5:55105617:TTGT:T	donor_loss	0.9900
5:55105618:TG:T	donor_loss	0.9900
5:55105619:GTAAG:G	donor_loss	0.9900
5:55105620:T:A	donor_loss	0.9900
5:55105621:A:AG	donor_loss	0.9900
5:55105622:AGTGC:A	donor_loss	0.9900

AlphaMissense

1712 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:55108226:G:C	W153C	0.996
5:55108226:G:T	W153C	0.996
5:55108302:T:A	C179S	0.994
5:55108303:G:C	C179S	0.994
5:55108356:T:A	C197S	0.991
5:55108357:G:C	C197S	0.991
5:55108209:T:A	C148S	0.988
5:55108210:G:C	C148S	0.988
5:55110152:G:C	W253C	0.988
5:55110152:G:T	W253C	0.988
5:55110075:T:C	F228L	0.987
5:55110077:T:A	F228L	0.987
5:55110077:T:G	F228L	0.987
5:55108224:T:A	W153R	0.986
5:55108224:T:C	W153R	0.986
5:55110033:A:C	S214R	0.986
5:55110035:C:A	S214R	0.986
5:55110035:C:G	S214R	0.986
5:55108303:G:A	C179Y	0.984
5:55105611:T:A	C70S	0.983
5:55105612:G:C	C70S	0.983
5:55107922:T:C	L115P	0.982
5:55105576:T:C	L58S	0.981
5:55108211:C:G	C148W	0.981
5:55108389:T:A	C208S	0.981
5:55108390:G:C	C208S	0.981
5:55108209:T:C	C148R	0.980
5:55107928:T:C	L117P	0.978
5:55110093:T:A	C234S	0.978
5:55110094:G:C	C234S	0.978

dbSNP variants (sampled 300 via entrez): RS1000055951 (5:55102264 G>T), RS1000166521 (5:55103610 G>A), RS1001078172 (5:55105041 G>A,T), RS1001683111 (5:55106707 C>G,T), RS1002112733 (5:55106445 C>T), RS1002180051 (5:55101154 G>A), RS1002211297 (5:55100888 C>T), RS1002303209 (5:55104104 A>G,T), RS1002713969 (5:55107989 C>G,T), RS1002755608 (5:55106407 C>A), RS1002762054 (5:55103891 A>C,G), RS1002805957 (5:55100669 A>G), RS1002915800 (5:55107604 G>A,C), RS1003217643 (5:55102315 G>A), RS1003860186 (5:55105609 A>C)

Disease associations

OMIM: gene MIM:140050 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4307 (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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
(+)-JQ1 compound	decreases expression	1
walrycin A	increases expression	1
Bortezomib	decreases expression	1
Acetaminophen	affects cotreatment, decreases expression	1
Aspirin	decreases expression	1
Vehicle Emissions	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Capsaicin	increases expression, increases secretion	1
Dichlorvos	decreases expression	1
Dietary Carbohydrates	affects cotreatment, decreases expression	1
Diuron	decreases expression	1
Lipopolysaccharides	decreases expression	1
Methotrexate	decreases expression	1
Nickel	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Ziram	decreases expression	1
Asbestos, Serpentine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Genistein	increases expression	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4344609	Binding	Substrate activity at Granzyme A (unknown origin) expressed in Pichia pastoris incubated for 30 mins by fluorescence based assay	Detection of Active Granzyme A in NK92 Cells with Fluorescent Activity-Based Probe. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7XJ	Abcam Raji GZMA KO	Cancer cell line	Male
CVCL_B9Y8	Abcam THP-1 GZMA KO	Cancer cell line	Male
CVCL_C7A2	Abcam PC-3 GZMA KO	Cancer cell line	Male

Clinical trials (associated diseases)

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