CASP2

protein-coding

caspase 2, the group of Caspases|Protein phosphatase 1 regulatory subunits|Caspase recruitment domain containing

Gene summary

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]

Previous symbols:

NEDD2

MANE transcript

NM_032982.4

Inheritance

ClinVar variants

P:5U:61B:18

Top phenotype

Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr7:143,288,215-143,307,696

External References & Databases

Ensembl (ENSG00000106144)

Transcript & Mutation Effects

hg38 • Region Span ~19.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 80, with variant lissencephalyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957999

Submitter: ClinGen

*CASP2* was first reported in relation to Intellectual Developmental Disorder, Autosomal Recessive 80, with Variant Lissencephaly, in 2024 (Uctepe et al., PMID: 37880421). 5 variants (2 nonsense, 2 frameshift, and 1 canonical splice site variant) that have been reported in 8 probands in 2 publications (PMIDs: 37880421, 39672921) are included in this curation. The mechanism of pathogenicity appears to be loss of function. No variant functional evidence or experimental evidence exists to support this gene-disease association. In summary, there is moderate evidence to support the gene-disease relationship between *CASP2* and Intellectual Developmental Disorder, Autosomal Recessive 80, with Variant Lissencephaly. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date September 21, 2026 (SOP Version 12).

intellectual developmental disorder, autosomal recessive 80, with variant lissencephalyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957999

Submitter: G2P

intellectual developmental disorder, autosomal recessive 80, with variant lissencephalyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957999

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 80, with variant lissencephalyAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 37880421

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CASP2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 51

not providedTotal: 14

Inborn genetic diseasesTotal: 5

CASP2-related disorderTotal: 5

Intellectual developmental disorder, autosomal recessive 80, with variant lissencephalyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032982.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	13 clinvar	2 clinvar	18
missense			53 clinvar	3 clinvar		56
nonsense	2 clinvar		1 clinvar			3
start loss						0
frameshift	1 clinvar	1 clinvar				2
splice donor/acceptor (+/-2bp)	1 clinvar		4 clinvar			5
Total	4	1	61	16	2	84

Highest pathogenic variant AF is 0.0000047889052

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032982.4	RefSeq	NP_116764.2	11	MANE Select
ENST00000310447.10	Ensembl	ENSP00000312664.5	11	MANE Select
NM_001224.5	RefSeq	NP_001215.1	9	Standard
NM_032983.4	RefSeq	NP_116765.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Apoptosis - Homo sapiens (human)
Apoptosis Modulation and Signaling
Parkinsons Disease Pathway
Apoptosis
Apoptotic Signaling Pathway

Biological Process

luteolysis
neural retina development
apoptotic process
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
brain development

Molecular Function

cysteine-type endopeptidase activity
protein binding
enzyme binding
protein domain specific binding
identical protein binding

Cellular Component

nucleus
cytoplasm
mitochondrion
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310447
Coding exons: 11
Length: 19482
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125748
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.497	233	255	0.913	0.0000158	2973
Missense (PolyPhen)		74	106.89	0.69231		1229
Synonymous	-0.551	107	100	1.07	0.00000632	865
Loss of Function	2.82	9	23.9	0.377	0.00000133	272

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000070	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the activation cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival.;

Recessive Scores

pRec: 0.213

Intolerance Scores

LoFtool: 0.574
RVIS EVS: -0.65
RVIS percentile EVS: 16.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium