CRACR2A
Chr 12calcium release activated channel regulator 2A
Also known as: EFCAB4B, RAB46
The CRACR2A protein is a calcium-binding protein that regulates store-operated calcium entry in T-cells by controlling the clustering and activation of CRAC channels (ORAI1 and STIM1) at plasma membrane-endoplasmic reticulum junctions. Mutations cause combined immunodeficiency with autoimmunity and hemophagocytic lymphohistiocytosis, inherited in an autosomal recessive pattern. The gene shows extremely strong constraint against loss-of-function variants (pLI near 1), indicating that heterozygous loss-of-function is likely incompatible with normal development.
Limited evidence — not for standalone diagnostic reporting
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
226 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 59 | 0 | 59 |
Likely Pathogenic | 0 | 0 | 4 | 0 | 4 |
VUS | 0 | 115 | 8 | 0 | 123 |
Likely Benign | 0 | 5 | 3 | 1 | 9 |
Benign | 0 | 5 | 12 | 2 | 19 |
| Total | 0 | 125 | 86 | 3 | 214 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
CRACR2A · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools