GeneBe

CASP4

protein-coding

caspase 4, the group of Caspase recruitment domain containing|Caspases

Gene summary

This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain and a large and small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This caspase is able to cleave and activate its own precursor protein, as well as caspase 1 precursor. When overexpressed, this gene induces cell apoptosis. Alternative splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001225.4

Inheritance

—

ClinVar variants

U:54B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr11:104,942,866-104,969,366

External References & Databases

Ensembl (ENSG00000196954)NCBI Gene (837)OMIM (602664)HGNC:1505GenCCUniProt (P49662)AlphaFoldClinVar (CASP4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~26.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CASP4 variants in ClinVar

2 Conditions Cataloged
not specifiedTotal: 50
not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001225.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
 2
missense
47
clinvar
4
clinvar
2
clinvar
 53
nonsense
0
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total00544361
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001225.4RefSeqNP_001216.18MANE Select
ENST00000444739.7EnsemblENSP00000388566.28MANE Select
NM_033306.3RefSeqNP_150649.17Standard
ENST00000393150.7EnsemblENSP00000376857.37Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • NOD-like receptor signaling pathway - Homo sapiens (human)
  • Apoptosis Modulation and Signaling
  • Apoptosis
  • Apoptotic Signaling Pathway
  • caspase cascade in apoptosis

Biological Process

  • proteolysis
  • apoptotic process
  • activation of cysteine-type endopeptidase activity involved in apoptotic process
  • inflammatory response
  • innate immune response

Molecular Function

  • cysteine-type endopeptidase activity
  • CARD domain binding
  • cysteine-type endopeptidase activity involved in apoptotic process
  • cysteine-type endopeptidase activity involved in apoptotic signaling pathway

Cellular Component

  • extracellular region
  • cytoplasm
  • mitochondrion
  • endoplasmic reticulum
  • endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000444739
Coding exons
8
Length
26571
Individuals with no LoFs
125521
Homozygous LoFs
1
Heterozygous LoFs
204
Defined
125726
p
0.000816
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1762012080.9660.00001072497
Missense (PolyPhen)5768.2980.83458855
Synonymous-1.328873.51.200.00000384691
Loss of Function1.011418.70.7479.80e-7221

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000370.00037rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish0.00560.0055notable
European (Non-Finnish)0.000650.00064rare
South Asian0.0000330.000033rare
Other0.000170.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Inflammatory caspase (PubMed:7797510, PubMed:23516580, PubMed:25119034). Essential effector of NLRP3 inflammasome- dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation, cholera enterotoxin subunit B and cytosolic LPS (PubMed:22246630, PubMed:26174085, PubMed:26173988, PubMed:26508369, PubMed:25964352). Independently of NLRP3 inflammasome and CASP1, promotes pyroptosis, through GSDMD cleavage and activation, and IL1A, IL18 and HMGB1 release in response to non-canonical inflammasome activators (PubMed:24879791, PubMed:25964352). Plays a crucial role in the restriction of Salmonella typhimurium replication in colonic epithelial cells during infection (PubMed:25121752). In later stages of the infection, LPS from cytosolic Salmonella triggers CASP4 activation, which ultimately results in pyroptosis of infected cells and their extrusion into the gut lumen, as well as in IL18 secretion. Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation. Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found Alzheimer's patient brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). Activated by direct binding to LPS without the need of an upstream sensor (PubMed:25119034). Does not directly process IL1B (PubMed:7743998, PubMed:7797592, PubMed:7797510). During non- canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590). {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:22246630, ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:24879791, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:25964352, ECO:0000269|PubMed:26173988, ECO:0000269|PubMed:26174085, ECO:0000269|PubMed:26508369, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:7743998, ECO:0000269|PubMed:7797510, ECO:0000269|PubMed:7797592}.;

Recessive Scores

pRec
0.246

Intolerance Scores

LoFtool
0.981
RVIS EVS
0.22
RVIS percentile EVS
68.44

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.909

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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