CLCN7

Chr 16ADAR

Cl-/H+ antiporter 7

Also known as: CLC-7, CLC7, HOD, OPTA2, OPTB4, PPP1R63

The product of this gene belongs to the CLC chloride channel family of proteins. Chloride channels play important roles in the plasma membrane and in intracellular organelles. This gene encodes chloride channel 7. Defects in this gene are the cause of osteopetrosis autosomal recessive type 4 (OPTB4), also called infantile malignant osteopetrosis type 2 as well as the cause of autosomal dominant osteopetrosis type 2 (OPTA2), also called autosomal dominant Albers-Schonberg disease or marble disease autosoml dominant. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. OPTA2 is the most common form of osteopetrosis, occurring in adolescence or adulthood. [provided by RefSeq, Jul 2008]

OMIMResearchGenerating clinical summary…
LOFmechanismAD/ARLOEUF 0.393 OMIM phenotypes
Clinical SummaryCLCN7
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Gene-Disease Validity (ClinGen)
autosomal dominant osteopetrosis 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint?
0.39LOEUF
pLI 0.272
Z-score 4.66
OE 0.23 (0.140.39)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?
2.11Z-score
OE missense 0.73 (0.670.80)
358 obs / 489.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?
LoF OE?0.23 (0.140.39)
00.351.4
Missense OE?0.73 (0.670.80)
00.61.4
Synonymous OE?1.26
01.21.6
LoF obs/exp: 10 / 43.0Missense obs/exp: 358 / 489.6Syn Z: -3.06
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveCLCN7-related osteopetrosisLOFAR
moderateCLCN7-related hypopigmentation, organomegaly, and delayed myelination and developmentOTHERAD

This gene — mechanism propensity

DN
0.7132th %ile
GOF
0.6833th %ile
LOF
0.3260th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-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.

DNprediction above median · 1 literature citation
GOFprediction above median · 1 literature citation

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

DNDominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients.1
GOFPrimary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants 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.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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