CASP8

Chr 2ARADSomatic

caspase 8

Also known as: ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5

NCBI Gene: 841 ENSG00000064012 UniProt: Q14790 OMIM: 601763

This gene encodes caspase-8, a cysteine protease that serves as a molecular switch for programmed cell death pathways including apoptosis, necroptosis, and pyroptosis, and regulates innate immunity. Mutations cause autosomal recessive caspase-8 deficiency syndrome, characterized by severe immunodeficiency with recurrent infections, lymphoproliferation, and variable features including failure to thrive and developmental delays in early childhood. The gene is highly intolerant to loss-of-function variants, indicating that complete loss of function is likely incompatible with normal development.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/AD/SomaticLOEUF 0.814 OMIM phenotypes

Clinical Summary— CASP8

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Gene-Disease Validity (ClinGen)

autoimmune lymphoproliferative syndrome type 2B · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

26 unique Pathogenic / Likely Pathogenic· 184 VUS of 408 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CASP8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.29

OE 0.51 (0.33–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.01Z-score

OE missense 0.83 (0.74–0.92)

226 obs / 273.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.33–0.81)

0≤0.351.4

Missense OE?0.83 (0.74–0.92)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 13 / 25.5Missense obs/exp: 226 / 273.0Syn Z: 0.41

This gene — mechanism propensity

0.75top 25%

GOF

0.73top 25%

LOF

0.1697th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFAlthough CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regar1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 23659359 ↗

ClinVar Variant Classifications

408 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic7

VUS184

Likely Benign140

Benign27

Conflicting11

Pathogenic

Likely Pathogenic

184

VUS

140

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	1	2	0	19
Likely Pathogenic	5	1	1	0	7
VUS	4	149	28	3	184
Likely Benign	3	10	49	78	140
Benign	0	2	22	3	27
Conflicting	—				11
Total	28	163	102	84	388

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

31 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap CASP8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →