CLCN7

Chr 16ADAR

chloride voltage-gated channel 7

NCBI Gene: 1186ENSG00000103249UniProt: P51798

Slowly voltage-gated channel mediating the exchange of chloride ions against protons (PubMed:18449189, PubMed:21527911). Functions as antiporter and contributes to the acidification of the lysosome lumen and may be involved in maintaining lysosomal pH (PubMed:18449189, PubMed:21527911, PubMed:31155284). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (By similarity). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (By similarity)

Primary Disease Associations & Inheritance

Hypopigmentation, organomegaly, and delayed myelination and developmentMIM #618541
AD
Osteopetrosis, autosomal dominant 2MIM #166600
AD
Osteopetrosis, autosomal recessive 4MIM #611490
AR
1523
ClinVar variants
44
Pathogenic / LP
0.27
pLI score
0
Active trials
Clinical Summary— CLCN7
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
44 Pathogenic / Likely Pathogenic· 225 VUS of 1523 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.39LOEUF
pLI 0.272
Z-score 4.66
OE 0.23 (0.14–0.39)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.11Z-score
OE missense 0.73 (0.67–0.80)
358 obs / 489.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.23 (0.14–0.39)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.67–0.80)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.26
0≤1.21.6
LoF obs/exp: 10 / 43.0Missense obs/exp: 358 / 489.6Syn Z: -3.06

ClinVar Variant Classifications

1523 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic27
VUS225
Likely Benign296
Benign3
Conflicting6
17
Pathogenic
27
Likely Pathogenic
225
VUS
296
Likely Benign
3
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
2
9
0
17
Likely Pathogenic
15
9
3
0
27
VUS
2
197
20
6
225
Likely Benign
0
5
161
130
296
Benign
0
0
2
1
3
Conflicting
—6
Total23213195137574

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.

Gene2Phenotype Curations

CLCN7-related osteopetrosis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

CLCN7-related hypopigmentation, organomegaly, and delayed myelination and development

moderate
ADUndeterminedAltered Gene Product Structure
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hypopigmentation, organomegaly, and delayed myelination and development

MIM #618541

Molecular basis of disorder known

Autosomal dominant

Osteopetrosis, autosomal dominant 2

MIM #166600

Molecular basis of disorder known

Autosomal dominant

Osteopetrosis, autosomal recessive 4

MIM #611490

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autosomal dominant osteopetrosis.
Polgreen LE et al.·Bone
2023Review
Gain-of-function variants in CLCN7 cause hypopigmentation and lysosomal storage disease.
Polovitskaya MM et al.·J Biol Chem
2024
Multisystem disorder associated with a pathogenic variant in CLCN7 in the absence of osteopetrosis.
Lee CL et al.·Mol Genet Genomic Med
2024Case report
Osteopetroses, emphasizing potential approaches to treatment.
Teti A et al.·Bone
2017Review
Genotype-phenotype analysis of selective failure of tooth eruption-A systematic review.
Guo X et al.·Clin Genet
2023Meta-analysis
Molecular Mechanisms of Craniofacial and Dental Abnormalities in Osteopetrosis.
Ma Y et al.·Int J Mol Sci
2023Review
CLCN7 polymorphisms and bone mineral density in healthy premenopausal white women and in white men.
Chu K et al.·Bone
2008
Osteopetrosis and related osteoclast disorders in adults: A review and knowledge gaps On behalf of the European calcified tissue society and ERN BOND.
Funck-Brentano T et al.·Eur J Med Genet
2024Review
CRISPR/Cas9-Mediated Gene Correction in Osteopetrosis Patient-Derived iPSCs.
Li D et al.·Front Biosci (Landmark Ed)
2023
Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations.
Pangrazio A et al.·Hum Mutat
2010
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools