CLCN6

Chr 1

Cl-/H+ antiporter 6

Also known as: CLC-6, CONRIBA

NCBI Gene: 1185 ENSG00000011021 UniProt: P51797

The protein functions as a voltage-gated chloride/proton antiporter that contributes to acidification of late endosome lumens. Mutations cause Neuronal ceroid lipofuscinosis 7, an autosomal recessive lysosomal storage disorder characterized by progressive neurodegeneration with seizures, vision loss, and cognitive decline typically beginning in late infancy to early childhood. The gene shows moderate constraint against loss-of-function variants, indicating intolerance to complete protein loss.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCeroid lipofuscinosis, neuronal, 15

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · neuronal ceroid lipofuscinosis 15 · AD · ClinGen 2026

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.61

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.000

Z-score 3.78

OE 0.42 (0.30–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.59Z-score

OE missense 0.81 (0.75–0.87)

439 obs / 543.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.30–0.61)

0≤0.351.4

Missense OE?0.81 (0.75–0.87)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 21 / 49.7Missense obs/exp: 439 / 543.5Syn Z: -0.89

Background carrier burden — how many people carry a rare variant somewhere in CLCN6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 77

1,207 rare PASS variants

Rare truncating (LoF)

1 in 1,800

159 rare PASS variants

Rare synonymous (reference)

1 in 82

537 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CLCN6. 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 99	1 in 2,000
South Asian	~43k	1 in 50	1 in 1,200
Remaining (unassigned)	~30k	1 in 62	1 in 2,200
European (Finnish)	~27k	1 in 140	1 in 5,300
Admixed American	~22k	1 in 49	1 in 1,200
African / African American	~21k	1 in 46	1 in 2,000
East Asian	~20k	1 in 46	1 in 1,400
Ashkenazi Jewish	~13k	1 in 610	1 in 900
Middle Eastern	~2,884	1 in 62	≈ 1 in 910

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.

Exome coverage (gnomAD): 22 of 23 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 23.? see exons ↓