CLCN3

Chr 4ARAD

Cl-/H+ antiporter 3

Also known as: CLC3, ClC-3, NEDHYBA, NEDSBA

NCBI Gene: 1182ENSG00000109572UniProt: P51790

This gene encodes a member of the voltage-gated chloride channel (ClC) family. The encoded protein is present in all cell types and localized in plasma membranes and in intracellular vesicles. It is a multi-pass membrane protein which contains a ClC domain and two additional C-terminal CBS (cystathionine beta-synthase) domains. The ClC domain catalyzes the selective flow of Cl- ions across cell membranes, and the CBS domain may have a regulatory function. This protein plays a role in both acidification and transmitter loading of GABAergic synaptic vesicles, and in smooth muscle cell activation and neointima formation. This protein is required for lysophosphatidic acid (LPA)-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. The protein activity is regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in glioma cells. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

Primary Disease Associations & Inheritance

?Neurodevelopmental disorder with seizures and brain abnormalitiesMIM #619517
AR
Neurodevelopmental disorder with hypotonia and brain abnormalitiesMIM #619512
AD
265
ClinVar variants
71
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CLCN3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
71 Pathogenic / Likely Pathogenic· 162 VUS of 265 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.22LOEUF
pLI 1.000
Z-score 5.37
OE 0.10 (0.05–0.22)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
4.37Z-score
OE missense 0.44 (0.39–0.49)
208 obs / 476.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.10 (0.05–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.44 (0.39–0.49)
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.0.86
0≤1.21.6
LoF obs/exp: 4 / 41.2Missense obs/exp: 208 / 476.8Syn Z: 1.47

ClinVar Variant Classifications

265 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic54
Likely Pathogenic17
VUS162
Likely Benign16
Benign2
54
Pathogenic
17
Likely Pathogenic
162
VUS
16
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
52
0
54
Likely Pathogenic
0
14
3
0
17
VUS
12
133
17
0
162
Likely Benign
0
5
3
8
16
Benign
0
0
1
1
2
Total13153769251

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CLCN3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CLCN3-related neurodevelopmental disorder with seizures and brain abnormalities

limited
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

CLCN3-related neurodevelopmental disorder with hypotonia and brain abnormalities

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Neurodevelopmental disorder with seizures and brain abnormalities

MIM #619517

Molecular basis of disorder known

Autosomal recessive

Neurodevelopmental disorder with hypotonia and brain abnormalities

MIM #619512

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Ontogeny of CLCN3 chloride channel gene expression in human pulmonary epithelium.
Lamb FS et al.·Am J Respir Cell Mol Biol
2001
Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders.
Duncan AR et al.·Am J Hum Genet
2021Case report
CLC-3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis.
Yoshikawa M et al.·Genes Cells
2002
Age-restricted functional and developmental differences of neonatal platelets.
Liu Z et al.·J Thromb Haemost
2022Functional
Disruption of ClC-3-mediated 2Cl(-)/H(+) exchange leads to behavioural deficits and thalamic atrophy.
Balduin C et al.·Sci Rep
2025
Shared genetic links between amyotrophic lateral sclerosis and obesity-related traits: a genome-wide association study.
Li C et al.·Neurobiol Aging
2021
Genetic insights into childhood-onset schizophrenia: The yield of clinical exome sequencing.
Alkelai A et al.·Schizophr Res
2023
Dominant Action of CLCN4 Neurodevelopmental Disease Variants in Heteromeric Endosomal ClC-3/ClC-4 Transporters.
Tettey-Matey A et al.·Cells
2025
Human Omental Mesothelial Cells Exhibit a Corneal Endothelial-Like Cell Phenotype for Tissue Engineering of a Corneal Endothelium Biomimetic.
Alió JL et al.·Invest Ophthalmol Vis Sci
2025
A new locus for autosomal recessive RP (RP29) mapping to chromosome 4q32-q34 in a Pakistani family.
Hameed A et al.·Invest Ophthalmol Vis Sci
2001
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