CASP8
protein-codingcaspase 8, the group of Caspases|Death effector domain containing|Ripoptosome|Death inducing signaling complex
Gene summary
This gene encodes 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, a large protease subunit, and a 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 protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~128.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011804
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011804
Submitter: ClinGen
CASP8 was FIRST reported in relation to autosomal recessive Caspase 8-related immune disorder in 2002 (Chun HJ et al. PMID:12353035). A review of the literature shows three main phenotypes in affected individuals: a lymphoproliferative pheontype, a immunodeficiency phenotype (characterized by sinuopulmonary bacterial infections and EBV/HSV/molluscum viruses, and an autommunune/autoinflammatory phenotype most notably very early onset IBD. At least two missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes genetic data, segregtion data, and extensive experimental data. Variants in this gene have been reported in at least 6 probands in 4 publications (PMIDs: 12353035, 25814141, 30267714, 41026346). The landmark study (PMID: 12353035) identified 2 siblings with a homozygous missense variant (R248W). A second report (PMID: 25814141) described 2 adult siblings with a homozygous variant (G445C) presenting with late-onset lymphocytic infiltration. There are reports of at veo-IBD documented in the literature (PMID: 30267714). Variants in this gene segregated with disease in additional family members across these consanguineous pedigrees. Summary of Case-Control Data This gene-disease relationship has been studied in at least 1 case-control study (PMID: 12353035) at the single variant level, primarily exploring the contribution of CASP8 polymorphisms to the susceptibility of the CEDS phenotype. Aggregate variant level case-control studies for this specific ultra-rare immunodeficiency are limited due to the small global patient population. Comment on statistics: Monogenic disease (CEDS) is driven strictly by rare, biallelic loss-of-function or damaging missense variants with clear segregation. The mechanism is homozygous loss of function. While Caspase-8 is pro-apoptotic, its deficiency in humans results in a paradox of both lymphoproliferation (failure to die) and immunodeficiency (failure of T/B/NK cell activation via the NF-κB pathway). Final Gene-Disease Validity Classification ● DEFINITIVE: In summary, there is definitive evidence to support the relationship between CASP8 and Autosomal Recessive Caspase-8 Deficiency State (CEDS). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time through the identification of distinct biallelic variants in multiple unrelated families. This classification was approved by the ClinGen Immune Dysregulation Gene Curation Expert Panel on the meeting date April 21, 2026 (SOP Version [12]).
Inheritance Pattern: AR
Disease ID:MONDO:0011804
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011804
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CASP8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001372051.1. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 85 | 1 | 88 | ||
| missense | 1 | 139 | 8 | 148 | ||
| nonsense | 6 | 3 | 9 | |||
| start loss | 0 | |||||
| frameshift | 5 | 2 | 2 | 9 | ||
| splice donor/acceptor (+/-2bp) | 2 | 8 | 10 | |||
| Total | 11 | 5 | 154 | 93 | 1 | 264 |
Highest pathogenic variant AF is 0.00003673399
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001358980.1 | 8 | MANE Select | |
| Ensembl | ENSP00000501268.1 | 8 | MANE Select | |
| RefSeq | NP_001073593.1 | 7 | Standard | |
| RefSeq | NP_001073594.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Legionellosis - Homo sapiens (human)
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
- Viral myocarditis - Homo sapiens (human)
- p53 signaling pathway - Homo sapiens (human)
Biological Process
- proteolysis
- apoptotic process
- activation of cysteine-type endopeptidase activity involved in apoptotic process
- cell surface receptor signaling pathway
- extrinsic apoptotic signaling pathway via death domain receptors
Molecular Function
- cysteine-type endopeptidase activity
- death receptor binding
- tumor necrosis factor receptor binding
- protein binding
- peptidase activity
Cellular Component
- nucleoplasm
- cytoplasm
- mitochondrion
- mitochondrial outer membrane
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000358485
- Coding exons
- 9
- Length
- 54269
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 25
- Defined
- 125748
- p
- 0.0000994
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.01 | 226 | 273 | 0.828 | 0.0000133 | 3585 |
| Missense (PolyPhen) | 50 | 87.17 | 0.5736 | 1178 | ||
| Synonymous | 0.407 | 98 | 103 | 0.949 | 0.00000527 | 967 |
| Loss of Function | 2.29 | 13 | 25.5 | 0.510 | 0.00000142 | 321 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000097 | 0.000097 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:9006941}.;
- Disease
- DISEASE: Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. {ECO:0000269|PubMed:12353035}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.671
Intolerance Scores
- LoFtool
- 0.274
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 57.31
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |