GZMH

Summary

GZMH (granzyme H, HGNC:4710) is a protein-coding gene on chromosome 14q12, encoding Granzyme H (P20718). Cytotoxic chymotrypsin-like serine protease with preference for bulky and aromatic residues at the P1 position and acidic residues at the P3’ and P4’ sites.

This gene encodes a member of the peptidase S1 family of serine proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate a chymotrypsin-like protease. This protein is reported to be constitutively expressed in the NK (natural killer) cells of the immune system and may play a role in the cytotoxic arm of the innate immune response by inducing target cell death and by directly cleaving substrates in pathogen-infected cells. This gene is present in a gene cluster with another member of the granzyme subfamily on chromosome 14.

Source: NCBI Gene 2999 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_033423

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4710
Approved symbol	GZMH
Name	granzyme H
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	CGL-2, CCP-X, CTLA1, CSP-C
Ensembl gene	ENSG00000100450
Ensembl biotype	protein_coding
OMIM	116831
Entrez	2999

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000216338, ENST00000382548, ENST00000557220, ENST00000877853

RefSeq mRNA: 3 — MANE Select: NM_033423 NM_001270780, NM_001270781, NM_033423

CCDS: CCDS59243, CCDS9632

Canonical transcript exons

ENST00000216338 — 5 exons

Exon	Start	End
ENSE00000654535	24607149	24607406
ENSE00000654537	24608265	24608412
ENSE00000889483	24609559	24609685
ENSE00001596918	24607612	24607747
ENSE00002535276	24606480	24606746

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 99.57.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.3830 / max 526.2967, expressed in 116 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142634	3.3830	116

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.57	gold quality
blood	UBERON:0000178	92.09	gold quality
spleen	UBERON:0002106	82.63	gold quality
bone marrow cell	CL:0002092	82.12	gold quality
bone marrow	UBERON:0002371	81.59	gold quality
periodontal ligament	UBERON:0008266	81.15	silver quality
endometrium epithelium	UBERON:0004811	79.92	gold quality
decidua	UBERON:0002450	78.86	gold quality
gall bladder	UBERON:0002110	78.11	gold quality
lymph node	UBERON:0000029	76.31	gold quality
leukocyte	CL:0000738	75.30	gold quality
right lung	UBERON:0002167	74.45	gold quality
palpebral conjunctiva	UBERON:0001812	74.34	gold quality
mononuclear cell	CL:0000842	72.97	gold quality
monocyte	CL:0000576	72.74	gold quality
upper lobe of left lung	UBERON:0008952	72.60	gold quality
upper lobe of lung	UBERON:0008948	71.17	gold quality
smooth muscle tissue	UBERON:0001135	69.72	gold quality
germinal epithelium of ovary	UBERON:0001304	69.19	silver quality
cervix squamous epithelium	UBERON:0006922	69.18	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	68.65	gold quality
frontal pole	UBERON:0002795	68.61	gold quality
vermiform appendix	UBERON:0001154	68.34	gold quality
trabecular bone tissue	UBERON:0002483	68.26	silver quality
lung	UBERON:0002048	67.96	gold quality
right lobe of liver	UBERON:0001114	67.81	gold quality
choroid plexus epithelium	UBERON:0003911	67.46	gold quality
rectum	UBERON:0001052	67.33	gold quality
right coronary artery	UBERON:0001625	67.23	gold quality
parietal pleura	UBERON:0002400	66.67	gold quality

Single-cell (SCXA)

Detected in 31 experiment(s), a significant marker in 30.

Experiment	Marker?	Max mean expression
E-GEOD-149689	yes	2570.85
E-MTAB-9467	yes	2335.19
E-MTAB-6505	yes	2334.18
E-GEOD-106540	yes	2288.09
E-CURD-55	yes	2124.35
E-HCAD-4	yes	1770.38
E-HCAD-1	yes	1769.38
E-CURD-77	yes	1743.48
E-GEOD-139324	yes	1642.94
E-MTAB-6678	yes	1450.01
E-MTAB-10553	yes	1384.04
E-MTAB-6308	yes	1356.70
E-CURD-122	yes	1354.14
E-HCAD-15	yes	1329.50
E-CURD-120	yes	1252.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting GZMH, 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-4650-5P	99.98	64.69	999
HSA-MIR-1972	97.67	67.38	1172
HSA-MIR-4474-5P	94.23	67.95	568

Literature-anchored findings (GeneRIF, showing 13)

• Granzyme C rapidly induces target cell death by attacking nuclear and mitochondrial targets and that these targets are distinct from those used by granzyme B to cause classical apoptosis. (PMID:12515723)
• granzyme H complements the pro-apoptotic function of granzyme B in human NK cells (PMID:15069086)
• Granzyme H destroys the function of critical adenoviral proteins required for viral DNA replication and granzyme B inhibition. (PMID:17363894)
• Expression levels of GzmH in naive natural killer cells and its killing ability support the role of the protease in triggering an alternative cell-death pathway in innate immunity. (PMID:17409270)
• GzmH may play an essential role in caspase-dependent pathogen clearance in the innate immunity that may complement the proapoptotic function of GzmB in human NK cells. (PMID:17765974)
• Granzyme H could have evolved a proteolytic specificity that both interferes directly with adenovirus replication and prevents the virus from blocking the potent pro-apoptotic activity of granzyme B. (PMID:17766182)
• Cleavage of La protein by granzyme H generates a COOH-terminal truncated form of La protein that loses nuclear localization and decreases hepatitis C virus-internal ribosome entry site-mediated translational activity. (PMID:19039329)
• GzmH suppresses viral replication through association with the hepatitis B virus x protein. (PMID:22156339)
• An unusual RKR motif (Arg39-Lys40-Arg41), conserved only in GzmH, helps define the S3’ and S4’ binding regions, indicating the preference for acidic residues at the P3’ and P4’ sites. (PMID:22156497)
• Upon reactive center loop cleavage at Phe-343,SERPINB1 covalently complexes with GzmH. SERPINB1 overexpression suppresses GzmH- or LAK cell-mediated cytotoxicity. Crystal structures show possible conformational changes in GzmH for the suicide inhibition. (PMID:23269243)
• Granzyme H did directly process DFF45, potentially leading to DNA damage. (PMID:23352961)
• Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma. (PMID:33737344)
• Natural Killer Cells Disrupt Nerve Fibers by Granzyme H in Atheriosclerotic Cerebral Small Vessel Disease. (PMID:36006802)

Cross-species orthologs

0 orthologs

Paralogs (6): CMA1 (ENSG00000092009), CTSG (ENSG00000100448), GZMB (ENSG00000100453), KLK6 (ENSG00000167755), KLK13 (ENSG00000167759), AZU1 (ENSG00000172232)

Protein

Protein identifiers

Granzyme H — P20718 (reviewed: P20718)

Alternative names: CCP-X, Cathepsin G-like 2, Cytotoxic T-lymphocyte proteinase, Cytotoxic serine protease C

All UniProt accessions (2): P20718, A0A0C4DGJ9

UniProt curated annotations — full annotation on UniProt →

Function. Cytotoxic chymotrypsin-like serine protease with preference for bulky and aromatic residues at the P1 position and acidic residues at the P3’ and P4’ sites. Probably necessary for target cell lysis in cell-mediated immune responses. Participates in the antiviral response via direct cleavage of several proteins essential for viral replication.

Subcellular location. Cytolytic granule.

Tissue specificity. Constitutively expressed in NK cells.

Activity regulation. Inhibited by SERPINB1.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P20718-1	1	yes
P20718-2	2
P20718-3	3

RefSeq proteins (3): NP_001257709, NP_001257710, NP_219491* (*=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.B59 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (42 total): strand 15, turn 5, helix 4, glycosylation site 3, disulfide bond 3, active site 3, splice variant 2, signal peptide 1, propeptide 1, sequence variant 1, sequence conflict 1, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3TK9	X-RAY DIFFRACTION	2.2
3TJV	X-RAY DIFFRACTION	2.4
3TJU	X-RAY DIFFRACTION	2.7
4GAW	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20718-F1	92.67	0.87

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): 64 (charge relay system); 108 (charge relay system); 202 (charge relay system)

Disulfide bonds (3): 49–65, 142–208, 172–187

Glycosylation sites (3): 179, 71, 104

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)

MSigDB gene sets: 112 (showing top): chr14q12, MARTINEZ_RB1_TARGETS_UP, GOBP_PROTEIN_MATURATION, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, MODULE_109, MORF_IL4, GNF2_IL2RB, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_CELL_KILLING, MARTINEZ_RB1_AND_TP53_TARGETS_UP, GNF2_PTPN4, GOBP_PROTEOLYSIS, SMID_BREAST_CANCER_LUMINAL_B_DN, GOMF_PEPTIDASE_ACTIVITY, GNF2_MATK

GO Biological Process (4): proteolysis (GO:0006508), apoptotic process (GO:0006915), killing of cells of another organism (GO:0031640), protein maturation (GO:0051604)

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), membrane (GO:0016020), cytolytic granule (GO:0044194), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide hormone metabolism	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell killing	1
disruption of cell in another organism	1
gene expression	1
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1
lysosome	1
lytic vacuole	1

Protein interactions and networks

STRING

1780 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GZMH	GNLY	P09325	809
GZMH	NKG7	Q16617	784
GZMH	CEBPE	Q15744	714
GZMH	PRF1	P14222	699
GZMH	CCL5	P13501	650
GZMH	FGFBP2	Q9BYJ0	607
GZMH	CTSW	P56202	540
GZMH	FASLG	P48023	539
GZMH	CD8A	P01732	529
GZMH	CD86	P42081	515
GZMH	CD80	P33681	507
GZMH	KLRB1	Q12918	489
GZMH	CD4	P01730	486
GZMH	CCR7	P32248	481
GZMH	TIGIT	Q495A1	480

IntAct

6 interactions, top by confidence:

A	B	Type	Score
DDX41	NOS1AP	psi-mi:“MI:0914”(association)	0.530
L4	GZMH	psi-mi:“MI:0194”(cleavage reaction)	0.440
GZMH	IPO13	psi-mi:“MI:0914”(association)	0.350
GZMH	DENND11	psi-mi:“MI:0914”(association)	0.350
GZMH	PCDH7	psi-mi:“MI:0914”(association)	0.350

BioGRID (73): GZMH (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), CBWD1 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), STK26 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), TUBA1A (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), FGF13 (Affinity Capture-MS), TUBA1C (Affinity Capture-MS), IPO13 (Affinity Capture-MS), SPNS1 (Affinity Capture-MS), TUBB4A (Affinity Capture-MS), MROH1 (Affinity Capture-MS), PASK (Affinity Capture-MS)

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: 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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	38
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

600 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24606743:CCCC:C	acceptor_gain	1.0000
14:24606744:CCC:C	acceptor_gain	1.0000
14:24606744:CCCC:C	acceptor_gain	1.0000
14:24606745:CCC:C	acceptor_gain	1.0000
14:24607606:CCTCA:C	donor_loss	1.0000
14:24607607:CTCAC:C	donor_loss	1.0000
14:24607608:TCAC:T	donor_loss	1.0000
14:24607609:CA:C	donor_loss	1.0000
14:24607610:A:AG	donor_loss	1.0000
14:24607611:C:CA	donor_loss	1.0000
14:24607743:TGGAG:T	acceptor_gain	1.0000
14:24607745:GAG:G	acceptor_gain	1.0000
14:24607748:C:CC	acceptor_gain	1.0000
14:24606742:TCCCC:T	acceptor_gain	0.9900
14:24606743:CCCCC:C	acceptor_gain	0.9900
14:24606745:CC:C	acceptor_gain	0.9900
14:24606746:CC:C	acceptor_gain	0.9900
14:24606746:CCT:C	acceptor_loss	0.9900
14:24606747:C:CC	acceptor_gain	0.9900
14:24606747:CT:C	acceptor_loss	0.9900
14:24606748:T:A	acceptor_loss	0.9900
14:24607150:TTGAA:T	donor_gain	0.9900
14:24607151:TGAA:T	donor_gain	0.9900
14:24607264:T:TA	donor_gain	0.9900
14:24607611:CCTG:C	donor_gain	0.9900
14:24607744:GGAG:G	acceptor_gain	0.9900
14:24607747:GC:G	acceptor_loss	0.9900
14:24607748:CTGC:C	acceptor_loss	0.9900
14:24607751:C:CT	acceptor_gain	0.9900
14:24608259:CCTTA:C	donor_loss	0.9900

AlphaMissense

1602 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24607305:C:A	W147C	0.984
14:24607305:C:G	W147C	0.984
14:24606639:G:C	F235L	0.969
14:24606639:G:T	F235L	0.969
14:24606641:A:G	F235L	0.969
14:24606630:C:A	W238C	0.968
14:24606630:C:G	W238C	0.968
14:24607321:C:G	C142S	0.967
14:24607322:A:T	C142S	0.967
14:24607307:A:G	W147R	0.966
14:24607307:A:T	W147R	0.966
14:24608274:C:G	C65S	0.965
14:24608275:A:T	C65S	0.965
14:24607628:T:A	D108V	0.960
14:24607628:T:G	D108A	0.958
14:24607627:G:C	D108E	0.954
14:24607627:G:T	D108E	0.954
14:24607186:C:G	C187S	0.952
14:24607187:A:T	C187S	0.952
14:24608294:A:C	F58L	0.950
14:24608294:A:T	F58L	0.950
14:24608296:A:G	F58L	0.950
14:24608292:A:T	V59E	0.949
14:24606632:A:G	W238R	0.948
14:24606632:A:T	W238R	0.948
14:24606721:C:G	C208S	0.943
14:24606722:A:T	C208S	0.943
14:24607320:G:C	C142W	0.943
14:24607629:C:G	D108H	0.942
14:24606741:G:C	D201E	0.940

dbSNP variants (sampled 300 via entrez): RS1002444071 (14:24608458 T>C), RS1002757318 (14:24608133 T>C), RS1002906611 (14:24608782 G>C), RS1003359856 (14:24609424 C>G), RS1003927680 (14:24606562 A>G), RS1004854732 (14:24606533 C>G,T), RS1004978380 (14:24606883 G>T), RS1005524578 (14:24609176 A>G), RS1006039063 (14:24608546 C>A), RS1006092912 (14:24608724 G>A,C), RS1006613397 (14:24610691 A>G), RS1006950740 (14:24610448 G>A), RS1007644669 (14:24609106 C>T), RS1008986659 (14:24606167 G>T), RS1009653511 (14:24606179 G>A)

Disease associations

OMIM: gene MIM:116831 | 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: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
GSK-J4	decreases expression	1
sodium arsenite	affects splicing, increases expression	1
di-n-butylphosphoric acid	affects expression	1
Benzo(a)pyrene	increases methylation	1
Lipopolysaccharides	decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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