LRRC8A
Chr 9ADleucine rich repeat containing 8 VRAC subunit A
Also known as: AGM5, HsLRRC8A, LRRC8, SWELL1
This protein functions as an essential component of the volume-regulated anion channel (VRAC), which maintains cellular volume in response to osmotic changes and is required for B-cell and T-cell development. Mutations cause autosomal dominant agammaglobulinemia type 5, an immunodeficiency disorder resulting from defects in B-cell maturation. The gene is highly constrained against loss-of-function variants (pLI = 0.94, LOEUF = 0.35), indicating intolerance to protein-truncating mutations.
Limited evidence — not for standalone diagnostic reporting
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). 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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
LRRC8A · 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