CASP3

Chr 4

caspase 3

Also known as: CPP32, CPP32B, SCA-1

NCBI Gene: 836 ENSG00000164305 UniProt: P42574 OMIM: 600636

The protein is a cysteine protease that serves as a major effector caspase in the execution phase of apoptosis, cleaving numerous cellular proteins including PARP1, huntingtin, and other caspases to mediate programmed cell death. Mutations cause a severe neurodevelopmental disorder with intellectual disability, microcephaly, and seizures, inherited in an autosomal recessive pattern. The gene shows moderate tolerance to loss-of-function variants (pLI 0.10, LOEUF 0.69), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a cysteine-aspartic acid protease that plays a central role in the execution-phase of cell apoptosis. The encoded protein cleaves and inactivates poly(ADP-ribose) polymerase while it cleaves and activates sterol regulatory element binding proteins as well as caspases 6, 7, and 9. This protein itself is processed by caspases 8, 9, and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimer's disease. [provided by RefSeq, Aug 2017]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

1122

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.100

Z-score 2.37

OE 0.30 (0.15–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.66Z-score

OE missense 0.63 (0.53–0.74)

99 obs / 157.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.15–0.69)

0≤0.351.4

Missense OE?0.63 (0.53–0.74)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 4 / 13.3Missense obs/exp: 99 / 157.6Syn Z: 1.31

Background carrier burden — how many people carry a rare variant somewhere in CASP3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 230

297 rare PASS variants

Rare truncating (LoF)

1 in 3,500

39 rare PASS variants

Rare synonymous (reference)

1 in 590

93 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CASP3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 240	1 in 3,400
South Asian	~43k	1 in 190	1 in 1,600
Remaining (unassigned)	~30k	1 in 260	1 in 3,700
European (Finnish)	~27k	1 in 1,600	≈ 1 in 13,000
Admixed American	~22k	1 in 290	≈ 1 in 5,700
African / African American	~21k	1 in 370	≈ 1 in 8,100
East Asian	~20k	1 in 170	1 in 1,100
Ashkenazi Jewish	~13k	1 in 540	none seen
Middle Eastern	~2,884	1 in 300	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 6 coding exons well covered in gnomAD exomes; exons 3, 4 marginal. Genomes: all 6.? see exons ↓