CLCN3

Chr 4

Cl-/H+ antiporter 3

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

NCBI Gene: 1182 ENSG00000109572 UniProt: P51790

The CLCN3 protein functions as an electrogenic H+/Cl- exchanger that mediates chloride-proton exchange across cell membranes and plays a critical role in acidification and neurotransmitter loading of GABAergic synaptic vesicles. Mutations cause neurodevelopmental disorders with seizures, hypotonia, and brain abnormalities, with both autosomal recessive and autosomal dominant inheritance patterns reported. This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.22), indicating that even single functional copies are critical for normal development.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNeurodevelopmental disorder with hypotonia and brain abnormalities

UniProtNeurodevelopmental disorder with seizures and brain abnormalities

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.22

LOEUF· LoF intol.

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.10 (0.05–0.22)

0≤0.351.4

Missense OE?0.44 (0.39–0.49)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 4 / 41.2Missense obs/exp: 208 / 476.8Syn Z: 1.47

Background carrier burden — how many people carry a rare variant somewhere in CLCN3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

688 rare PASS variants

Rare truncating (LoF)

1 in 4,000

63 rare PASS variants

Rare synonymous (reference)

1 in 150

374 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CLCN3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 3,500
South Asian	~43k	1 in 170	1 in 4,800
Remaining (unassigned)	~30k	1 in 130	≈ 1 in 9,600
European (Finnish)	~27k	1 in 260	≈ 1 in 13,000
Admixed American	~22k	1 in 160	≈ 1 in 11,000
African / African American	~21k	1 in 95	1 in 2,100
East Asian	~20k	1 in 150	1 in 2,600
Ashkenazi Jewish	~13k	1 in 280	none seen
Middle Eastern	~2,884	1 in 140	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.