CLCN7
Chr 16ADARCl-/H+ antiporter 7
Also known as: CLC-7, CLC7, HOD, OPTA2, OPTB4, PPP1R63
Chloride channel 7 is a slowly voltage-gated channel that exchanges chloride ions for protons, contributing to lysosomal acidification and pH maintenance. Mutations cause osteopetrosis with abnormally dense bones due to defective bone resorption, presenting as severe infantile malignant osteopetrosis in the autosomal recessive form or milder adolescent/adult-onset disease in the autosomal dominant form. Some patients also develop hypopigmentation, organomegaly, and delayed myelination with developmental delays.
Definitive — sufficient evidence for diagnostic panels
3 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Moderately missense-constrained (top ~2.5%)
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative 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.
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
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 | 3 | 1 | 2 | 0 | 6 |
Likely Pathogenic | 12 | 4 | 0 | 0 | 16 |
VUS | 2 | 105 | 13 | 3 | 123 |
Likely Benign | 0 | 2 | 82 | 67 | 151 |
Benign | 0 | 0 | 1 | 1 | 2 |
Conflicting | — | 2 | |||
| Total | 17 | 112 | 98 | 71 | 300 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
CLCN7 · 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