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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein which 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 which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 3 and 7, and the protein itself is processed by caspase 8. Mutations in this gene are associated with type IIA autoimmune lymphoproliferative syndrome, non-Hodgkin lymphoma and gastric cancer. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 397 VUS of 655 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CASP10

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?

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 OE?0.88 (0.61–1.29)

0≤0.351.4

Missense OE?1.00 (0.90–1.10)

0≤0.61.4

Synonymous OE?1.03

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

This gene — mechanism propensity

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 studi1

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

References

1.PMID 16446975 ↗

ClinVar Variant Classifications

655 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic1

VUS397

Likely Benign164

Benign62

Conflicting17

Pathogenic

Likely Pathogenic

397

VUS

164

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	1	0	0	4
Likely Pathogenic	1	0	0	0	1
VUS	34	278	81	4	397
Likely Benign	3	7	58	96	164
Benign	0	3	56	3	62
Conflicting	—				17
Total	41	289	195	103	645

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 CASP10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →