CASP2

Chr 7AR

caspase 2

Also known as: CASP-2, ICH1, MRT80, NEDD-2, NEDD2, PPP1R57

NCBI Gene: 835 ENSG00000106144 UniProt: P42575 OMIM: 600639

The protein is a cysteine-aspartic acid protease (caspase) that regulates apoptosis by forming the PIDDosome complex with PIDD1 and CRADD, which triggers cell death in response to DNA damage and other cellular stress. Biallelic mutations cause autosomal recessive intellectual developmental disorder with variant lissencephaly, affecting brain development and cognitive function. The gene is highly constrained against loss-of-function variants (LOEUF 0.658), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Caspases mediate cellular apoptosis through the proteolytic cleavage of specific protein substrates. The encoded protein may function in stress-induced cell death pathways, cell cycle maintenance, and the suppression of tumorigenesis. Increased expression of this gene may play a role in neurodegenerative disorders including Alzheimer's disease, Huntington's disease and temporal lobe epilepsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.661 OMIM phenotype

Clinical Summary— CASP2

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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· 45 VUS of 89 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.002

Z-score 2.82

OE 0.38 (0.23–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.50Z-score

OE missense 0.91 (0.82–1.02)

233 obs / 255.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.23–0.66)

0≤0.351.4

Missense OE?0.91 (0.82–1.02)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 9 / 23.9Missense obs/exp: 233 / 255.3Syn Z: -0.55

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateCASP2-related developmental disorder with lissencephalyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6841th %ile

GOF

0.73top 25%

LOF

0.2581th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

89 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic1

VUS45

Likely Benign12

Benign2

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	0	0	0	4
Likely Pathogenic	1	0	0	0	1
VUS	0	45	0	0	45
Likely Benign	0	2	1	9	12
Benign	0	0	0	2	2
Conflicting	—				1
Total	5	47	1	11	65

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

View in ClinVar →

48 pathogenic / likely-pathogenic (of 56) ClinVar copy-number / structural variants overlap CASP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →