CRACR2A
protein-codingcalcium release activated channel regulator 2A, the group of EF-hand domain containing
Gene summary
Enables G protein activity and calcium ion binding activity. Involved in several processes, including positive regulation of JNK cascade; positive regulation of monoatomic ion transport; and store-operated calcium entry. Located in several cellular components, including Golgi apparatus; Weibel-Palade body; and immunological synapse. [provided by Alliance of Genome Resources, Jun 2026]
- EFCAB4B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~158.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015131
Submitter: ClinGen
*CRACR2A* was first reported in relation to autosomal recessive combined immunodeficiency in 2021 (Wu B, et al., 2021, PMID: 34908525). The calcium release-activated calcium channel regulator 2A (*CRACR2A*) was identified as a protein that binds ORAI1/STIM1 and stabilizes their interaction to mediate store-operated Ca2+ entry (SOCE) in T cells. *CRACR2A* encodes a large Rab GTPase that is expressed abundantly in T cells and acts as a signal transmitter between T cell receptor stimulation and activation of the Ca2+-NFAT and JNK-AP1 pathways. Two isoforms of the protein are expressed in T cells, a short cytoplasmic isoform CRACR2A-c, which was originally shown to bind ORAI1/STIM1 and stabilize their interaction, and a longer isoform CRACR2A-a, that is a Rab GTPase. The mechanism of pathogenicity appears to be biallelic loss of function and the resulting clinical phenotype is an antibody deficiency, although detailed immunological investigations show a combined immune defect with evidence of progressive lymphopenia and impaired T cell activation. Genetic evidence is available from a single proband (PMID: 34908525) with compound heterozygous missense and nonsense variants. Experimentally, this gene-disease relationship is supported by its interaction with ORAI1/STIM1 (PMID: 34908525), its function in T cells (PMID: 27016526), which is altered in patient cells as well as CRISPR/Cas9 modified Jurkat T cells (PMID: 34908525), resulting in reduced cytokine production. Furthermore, T cell-specific deletion of Cracr2a in Cracr2afl/fl mice showed defects in SOCE as well as JNK-phosphorylation, and thereby, reduction in cytokine (IFN-γ) production, suggesting conserved function of *CRACR2A* in mouse and human T cells (PMID: 29987160). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CRACR2A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001144958.2. 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 | 1 | 1 | 2 | |||
| missense | 120 | 6 | 126 | |||
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 126 | 7 | 0 | 133 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001138430.1 | 17 | MANE Select | |
| Ensembl | ENSP00000409382.2 | 17 | MANE Select | |
| RefSeq | NP_116069.1 | 8 | Standard | |
| Ensembl | ENSP00000252322.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vitamin D Receptor Pathway
- Neutrophil degranulation
- Innate Immune System
- Immune System
Biological Process
- store-operated calcium entry
- adaptive immune response
- activation of store-operated calcium channel activity
- neutrophil degranulation
- positive regulation of calcium ion transport
Molecular Function
- calcium ion binding
- protein binding
Cellular Component
- extracellular region
- cytoplasm
- membrane
- specific granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000440314
- Coding exons
- 17
- Length
- 158187
- Individuals with no LoFs
- 125622
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 126
- Defined
- 125748
- p
- 0.000501
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.928 | 357 | 410 | 0.871 | 0.0000235 | 4784 |
| Missense (PolyPhen) | 117 | 136.27 | 0.8586 | 1742 | ||
| Synonymous | 0.873 | 155 | 169 | 0.915 | 0.00000975 | 1387 |
| Loss of Function | 2.22 | 24 | 39.0 | 0.616 | 0.00000174 | 468 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00041 | 0.00040 | rare |
| Ashkenazi Jewish | 0.0058 | 0.0058 | notable |
| East Asian | 0.000055 | 0.000054 | rare |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.00025 | 0.00025 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00066 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Ca(2+)-binding protein that plays a key role in store- operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation. Acts as a cytoplasmic calcium-sensor that facilitates the clustering of ORAI1 and STIM1 at the junctional regions between the plasma membrane and the endoplasmic reticulum upon low Ca(2+) concentration. It thereby regulates CRAC channel activation, including translocation and clustering of ORAI1 and STIM1. Upon increase of cytoplasmic Ca(2+) resulting from opening of CRAC channels, dissociates from ORAI1 and STIM1, thereby destabilizing the ORAI1-STIM1 complex. {ECO:0000269|PubMed:20418871}.;
Recessive Scores
- pRec
- 0.100
Intolerance Scores
- RVIS EVS
- 1.85
- RVIS percentile EVS
- 97.12
Essentials
- Essential (gene trap)
- N