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.

OMIM ResearchSummary from RefSeq, UniProt

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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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 OE0.51 (0.33–0.81)

0≤0.351.4

Missense OE0.83 (0.74–0.92)

0≤0.61.4

Synonymous OE0.95

0≤1.21.6

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

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 regarPMID:23659359

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