CASP10

Chr 2AD

caspase 10

Also known as: ALPS2, FLICE-2, FLICE2, MCH4

NCBI Gene: 843 ENSG00000003400 UniProt: Q92851 OMIM: 601762

The CASP10 protein is a caspase that cleaves and activates downstream effector caspases (including caspases 3, 6, 7, 8, and 9) in the apoptotic execution pathway and is recruited to Fas and TNFR-1 death receptors. Mutations cause autosomal dominant autoimmune lymphoproliferative syndrome type II, characterized by defective lymphocyte apoptosis leading to lymphoproliferation and autoimmunity. The gene shows very low constraint against loss-of-function variants (pLI near zero), suggesting that complete loss of function may be tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

DNmechanismADLOEUF 1.293 OMIM phenotypes

Clinical Summary— CASP10

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Gene-Disease Validity (ClinGen)

autoimmune lymphoproliferative syndrome type 2A · ADLimited

Limited evidence — not for standalone diagnostic reporting

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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

1.29LOEUF

pLI 0.000

Z-score 0.53

OE 0.88 (0.61–1.29)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

0.03Z-score

OE missense 1.00 (0.90–1.10)

271 obs / 272.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.88 (0.61–1.29)

0≤0.351.4

Missense OE1.00 (0.90–1.10)

0≤0.61.4

Synonymous OE1.03

0≤1.21.6

LoF obs/exp: 19 / 21.7Missense obs/exp: 271 / 272.2Syn Z: -0.23

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCASP10-related autoimmune lymphoproliferative syndromeDNAD

0.76top 25%

GOF

0.72top 25%

LOF

0.2092th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction 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

DNTheir mother and a third sister were mutation carriers and asymptomatic at the time of evaluation, but showed defective T cell apoptosis in vitro, increased numbers of double-negative T cells, and positive direct antiglobulin IgG tests and antithyroid antibodies. In vitro functional expression studiPMID:16446975

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