GJA8
Chr 1ADgap junction protein alpha 8
Also known as: CAE, CAE1, CTRCT1, CX50, CZP1, MP70
This gene encodes connexin 50, a transmembrane protein that forms gap junction channels connecting lens fiber cells and is essential for lens growth and maturation. Mutations cause autosomal dominant cataracts of multiple types, including zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. The gene shows minimal constraint against loss-of-function variants (pLI 0.002), suggesting tolerance to complete protein loss.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. 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.
ClinVar Variant Classifications
300 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 | 6 | 136 | 0 | 142 |
Likely Pathogenic | 2 | 17 | 12 | 0 | 31 |
VUS | 8 | 67 | 9 | 0 | 84 |
Likely Benign | 0 | 4 | 1 | 14 | 19 |
Benign | 0 | 1 | 6 | 0 | 7 |
Conflicting | — | 16 | |||
| Total | 10 | 95 | 164 | 14 | 299 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
GJA8 · 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