CLCN6

Summary

CLCN6 (Cl-/H+ antiporter 6, HGNC:2024) is a protein-coding gene on chromosome 1p36.22, encoding H(+)/Cl(-) exchange transporter 6 (P51797). Voltage-gated channel mediating the exchange of chloride ions against protons.

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.

Source: NCBI Gene 1185 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities (Strong, GenCC)
• GWAS associations: 57
• Clinical variants (ClinVar): 1,059 total — 1 pathogenic
• Phenotypes (HPO): 27
• MANE Select transcript: NM_001286

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2024
Approved symbol	CLCN6
Name	Cl-/H+ antiporter 6
Location	1p36.22
Locus type	gene with protein product
Status	Approved
Aliases	CLC-6, KIAA0046, ClC-6
Ensembl gene	ENSG00000011021
Ensembl biotype	protein_coding
OMIM	602726
Entrez	1185

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 5 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000312413, ENST00000346436, ENST00000376490, ENST00000376491, ENST00000376492, ENST00000376496, ENST00000376497, ENST00000400892, ENST00000446542, ENST00000494028, ENST00000910827, ENST00000918075

RefSeq mRNA: 2 — MANE Select: NM_001286 NM_001256959, NM_001286

CCDS: CCDS138, CCDS57972

Canonical transcript exons

ENST00000346436 — 23 exons

Exon	Start	End
ENSE00001770331	11828458	11828624
ENSE00001820127	11806191	11806349
ENSE00003468465	11833877	11834030
ENSE00003536687	11822695	11822801
ENSE00003542357	11824486	11824553
ENSE00003546374	11815846	11815911
ENSE00003548910	11823707	11823833
ENSE00003561762	11807131	11807190
ENSE00003567257	11833515	11833638
ENSE00003580593	11826156	11826214
ENSE00003587774	11819488	11819554
ENSE00003589187	11827089	11827221
ENSE00003602758	11840143	11843130
ENSE00003688584	11816615	11816680
ENSE00003689831	11828106	11828219
ENSE00003712057	11835967	11836153
ENSE00003713487	11837343	11837499
ENSE00003728763	11838335	11838442
ENSE00003730914	11836999	11837156
ENSE00003735813	11834484	11834590
ENSE00003752281	11838535	11838660
ENSE00003752804	11829196	11829322
ENSE00003753248	11834236	11834395

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 93.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.7713 / max 129.1825, expressed in 1752 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
649	7.8898	1722
648	1.8815	927

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	93.44	gold quality
left testis	UBERON:0004533	92.71	gold quality
right atrium auricular region	UBERON:0006631	92.71	gold quality
adenohypophysis	UBERON:0002196	91.06	gold quality
cardiac atrium	UBERON:0002081	90.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.39	gold quality
sural nerve	UBERON:0015488	90.31	gold quality
testis	UBERON:0000473	89.92	gold quality
cerebellar hemisphere	UBERON:0002245	89.91	gold quality
middle temporal gyrus	UBERON:0002771	89.91	gold quality
cerebellar cortex	UBERON:0002129	89.82	gold quality
prefrontal cortex	UBERON:0000451	89.66	gold quality
cingulate cortex	UBERON:0003027	89.58	gold quality
anterior cingulate cortex	UBERON:0009835	89.55	gold quality
pituitary gland	UBERON:0000007	89.54	gold quality
right frontal lobe	UBERON:0002810	89.54	gold quality
frontal pole	UBERON:0002795	89.27	gold quality
hypothalamus	UBERON:0001898	89.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.68	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.68	gold quality
Brodmann (1909) area 10	UBERON:0013541	88.65	gold quality
cerebellum	UBERON:0002037	88.49	gold quality
left ovary	UBERON:0002119	88.33	gold quality
right adrenal gland cortex	UBERON:0035827	88.32	gold quality
right ovary	UBERON:0002118	88.31	gold quality
neocortex	UBERON:0001950	88.29	gold quality
frontal cortex	UBERON:0001870	88.17	gold quality
metanephros cortex	UBERON:0010533	88.11	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.87	gold quality
right adrenal gland	UBERON:0001233	87.85	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

127 targeting CLCN6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-148A-3P	99.74	73.77	1700

Literature-anchored findings (GeneRIF, showing 7)

• differential sorting of endogenous (late endosomal) versus overexpressed (early and recycling endosomal) ClC-6 is reminiscent of that of other late endosomal/lysosomal membrane proteins (PMID:17534424)
• late endosomal ClC-6 mediates proton/chloride countertransport in heterologous plasma membrane expression (PMID:20466723)
• A non-synonymous single nucleotide variation (SNV) was identified in the voltage-sensitive chloride channel 6 gene. (PMID:25794116)
• These findings implicate the effect of rare coding variants in CLCN6 in Blood Pressure variation and offer new insights into Blood Pressure regulation. (PMID:26658788)
• A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl(-)/H(+)-Exchanger, Causes Early-Onset Neurodegeneration. (PMID:33217309)
• Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia. (PMID:33737586)
• Molecular basis of ClC-6 function and its impairment in human disease. (PMID:37831762)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	clcn6	ENSDARG00000032577
mus_musculus	Clcn6	ENSMUSG00000029016
rattus_norvegicus	Clcn6	ENSRNOG00000008345
drosophila_melanogaster	ClC-c	FBGN0036566
caenorhabditis_elegans		WBGENE00000532

Paralogs (8): CLCN4 (ENSG00000073464), CLCN7 (ENSG00000103249), CLCN3 (ENSG00000109572), CLCN2 (ENSG00000114859), CLCN5 (ENSG00000171365), CLCNKB (ENSG00000184908), CLCNKA (ENSG00000186510), CLCN1 (ENSG00000188037)

Protein

Protein identifiers

H(+)/Cl(-) exchange transporter 6 — P51797 (reviewed: P51797)

Alternative names: Chloride channel protein 6, Chloride transport protein 6

All UniProt accessions (2): P51797, A0A3B3IRY0

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated channel mediating the exchange of chloride ions against protons. Functions as antiporter and contributes to the acidification of the late endosome lumen. The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The presence of conserved gating glutamate residues is typical for family members that function as antiporters.

Subcellular location. Late endosome membrane.

Tissue specificity. Testis, ovary, small intestine, brain and skeletal muscle. Low level expression in aortic and coronary vascular smooth muscle cells, and aortic endothelial cells. Isoform 3 is only detected in kidney.

Post-translational modifications. N-glycosylated on several asparagine residues.

Disease relevance. Ceroid lipofuscinosis, neuronal, 15 (CLN15) [MIM:619173] An autosomal dominant, progressive, neurodegenerative disorder characterized by severe global developmental delay, impaired intellectual development, poor or absent speech, hypotonia, impaired motor development, respiratory insufficiency, and feeding difficulties. Most patients have visual defects, including cortical visual blindness, nystagmus, and esotropia. Brain imaging shows abnormalities affecting the brainstem, cerebellum, and corticospinal tracts. Disease onset is in infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the chloride channel (TC 2.A.49) family. ClC-6/CLCN6 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
P51797-1	1, A, Clc-6a	yes
P51797-2	2, B, ClC-6b, D2-A1
P51797-3	3, C, ClC-6c, D1-A1
P51797-4	4, D, ClC-6d, D1-A2
P51797-5	5
P51797-6	6

RefSeq proteins (2): NP_001243888, NP_001277* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000644	CBS_dom	Domain
IPR001807	ClC	Family
IPR002248	Cl_channel-6	Family
IPR014743	Cl-channel_core	Homologous_superfamily
IPR046342	CBS_dom_sf	Homologous_superfamily
IPR051280	Cl-channel/antiporter	Family

Pfam: PF00571, PF00654

Catalyzed reactions (Rhea), 1 shown:

• 2 chloride(in) + H(+)(out) = 2 chloride(out) + H(+)(in) (RHEA:29567)

UniProt features (115 total): helix 35, strand 17, transmembrane region 10, splice variant 8, turn 7, intramembrane region 7, mutagenesis site 7, binding site 5, short sequence motif 3, glycosylation site 3, sequence conflict 3, topological domain 2, domain 2, site 2, sequence variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8JPO	ELECTRON MICROSCOPY	3.4
8JPR	ELECTRON MICROSCOPY	3.4
8JPJ	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51797-F1	77.43	0.34

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 200 (mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking h(+) and cl(-) transport); 267 (mediates proton transfer from the protein to the inner aqueous phase)

Ligand- & substrate-binding residues (5): 157; 489; 576; 630–632; 849–852

Post-translational modifications (1): 773

Glycosylation sites (3): 410, 422, 432

Mutagenesis-validated functional residues (7):

Position	Phenotype
157	increases the nitrate/chloride conductance ratio.
200	abolishes proton transport, but not chloride transport. strongly increases anion current; when associated with s-576.
267	loss of proton and chloride transport.
410	abolishes n-glycosylation; when associated with a-422 and a-432.
422	abolishes n-glycosylation; when associated with a-410 and a-432.
432	abolishes n-glycosylation; when associated with a-410 and a-422.
576	strongly increases anion current; when associated with a-200.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-6802952	Signaling by BRAF and RAF1 fusions

MSigDB gene sets: 211 (showing top): BROWNE_HCMV_INFECTION_6HR_DN, GOCC_VACUOLAR_MEMBRANE, GOBP_INORGANIC_ANION_TRANSPORT, GGGTGGRR_PAX4_03, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_CHLORIDE_TRANSPORT, GOBP_REGULATION_OF_CELL_SIZE, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_CELL_VOLUME_HOMEOSTASIS, DANG_BOUND_BY_MYC, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_RESPONSE_TO_MECHANICAL_STIMULUS, GOCC_LATE_ENDOSOME_MEMBRANE

GO Biological Process (8): chloride transport (GO:0006821), cell volume homeostasis (GO:0006884), signal transduction (GO:0007165), response to mechanical stimulus (GO:0009612), monoatomic ion transmembrane transport (GO:0034220), monoatomic ion transport (GO:0006811), transmembrane transport (GO:0055085), chloride transmembrane transport (GO:1902476)

GO Molecular Function (6): voltage-gated chloride channel activity (GO:0005247), ATP binding (GO:0005524), antiporter activity (GO:0015297), nucleotide binding (GO:0000166), chloride channel activity (GO:0005254), chloride transmembrane transporter activity (GO:0015108)

GO Cellular Component (5): lysosomal membrane (GO:0005765), endosome membrane (GO:0010008), membrane (GO:0016020), late endosome membrane (GO:0031902), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Oncogenic MAPK signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
transport	2
monoatomic anion transport	1
inorganic anion transport	1
regulation of cell size	1
cellular homeostasis	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to external stimulus	1
response to abiotic stimulus	1
monoatomic ion transport	1
transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
chloride channel activity	1
voltage-gated monoatomic anion channel activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
secondary active transmembrane transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
monoatomic anion transmembrane transporter activity	1
chloride transmembrane transport	1
lysosome	1
lytic vacuole membrane	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cellular anatomical structure	1
late endosome	1
endosome membrane	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

1019 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCN6	MTHFR	P42898	814
CLCN6	OSTM1	Q86WC4	810
CLCN6	PPT1	P50897	762
CLCN6	FAM131B	Q86XD5	722
CLCN6	RNF130	Q86XS8	698
CLCN6	MKRN1	Q9UHC7	639
CLCN6	AGTRAP	Q6RW13	571
CLCN6	KIAA1549	Q9HCM3	554
CLCN6	GNAI1	P04898	530
CLCN6	CLN6	Q9NWW5	519
CLCN6	SGSH	P51688	517
CLCN6	BRAF	P15056	508
CLCN6	TRAK1	Q9UPV9	492
CLCN6	CLN5	O75503	488
CLCN6	MFSD8	Q8NHS3	488

IntAct

8 interactions, top by confidence:

A	B	Type	Score
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
CLCN6	ERBB2	psi-mi:“MI:0915”(physical association)	0.370
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
ATG4C	SPAG9	psi-mi:“MI:0914”(association)	0.350
MFSD12	SNAP23	psi-mi:“MI:0914”(association)	0.350
SLC30A10	GOLIM4	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): CLCN6 (Affinity Capture-RNA), CLCN6 (Two-hybrid), CLCN6 (Affinity Capture-MS), CLCN6 (Affinity Capture-RNA), CLCN6 (Affinity Capture-MS), CLCN6 (Affinity Capture-MS), CLCN6 (Affinity Capture-MS), CLCN6 (Co-fractionation), OSBPL1A (Co-fractionation), SIDT2 (Co-fractionation), CLCN6 (Affinity Capture-MS), CLCN6 (Affinity Capture-MS), CLCN6 (Affinity Capture-RNA), CLCN6 (Affinity Capture-MS), CLCN6 (Affinity Capture-MS)

ESM2 similar proteins: A0A075B734, A1L272, A2IBY8, A8W649, A9Y006, D4A7H1, E7EXX2, F7B113, O14520, O35454, O54794, O62735, O94956, P34080, P35525, P41181, P47862, P47863, P47864, P51789, P51797, P56402, P56403, P79099, Q06495, Q06496, Q08DE6, Q4R691, Q5PQL3, Q62052, Q866S3, Q8BLV3, Q8BXB6, Q8BZ00, Q8IVB4, Q8K078, Q8MIQ9, Q8R2N1, Q8TCT8, Q921R8

Diamond homologs: A1A7K1, A4TPW7, A5F0D5, A6T4V9, A7FM08, A7MGR4, A7N6K9, A7ZHP7, A7ZWA3, A8ALD3, A9MPK6, A9N0Q1, A9R1E4, B1IQI5, B1JK21, B1LGV8, B1XD25, B2K549, B2U300, B4SUY5, B4TK31, B4TXQ7, B5BL83, B5F8R6, B5FJ02, B5R3G7, B5RHE1, B5Y1L4, B5Z0D5, B6HZD1, B7LGL7, B7LWB6, B7M196, B7MBD8, B7MP17, B7N824, B7NIB8, B7UIK2, C0Q5R6, C3LVE3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1059 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	552
Likely benign	428
Benign	39

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3338632	NM_001286.5(CLCN6):c.599A>C (p.Glu200Ala)	Pathogenic

SpliceAI

4364 predictions. Top by Δscore:

Variant	Effect	Δscore
1:11806346:GCTG:G	donor_gain	1.0000
1:11806350:G:GA	donor_loss	1.0000
1:11806350:G:GG	donor_gain	1.0000
1:11806351:T:G	donor_loss	1.0000
1:11815845:GA:G	acceptor_gain	1.0000
1:11815907:ATAAG:A	donor_loss	1.0000
1:11815908:TAAG:T	donor_loss	1.0000
1:11815909:AAG:A	donor_loss	1.0000
1:11815910:AGGT:A	donor_loss	1.0000
1:11815911:GGTG:G	donor_loss	1.0000
1:11815912:G:GC	donor_loss	1.0000
1:11815913:T:G	donor_loss	1.0000
1:11816614:GAAA:G	acceptor_gain	1.0000
1:11823705:AGCC:A	acceptor_gain	1.0000
1:11823706:GCCG:G	acceptor_gain	1.0000
1:11824475:A:AG	acceptor_gain	1.0000
1:11824475:ACCCT:A	acceptor_gain	1.0000
1:11824476:C:G	acceptor_gain	1.0000
1:11824479:T:A	acceptor_gain	1.0000
1:11824483:CAG:C	acceptor_loss	1.0000
1:11824484:A:AG	acceptor_gain	1.0000
1:11824484:AG:A	acceptor_gain	1.0000
1:11824484:AGG:A	acceptor_gain	1.0000
1:11824484:AGGGC:A	acceptor_loss	1.0000
1:11824485:G:GT	acceptor_gain	1.0000
1:11824485:GG:G	acceptor_gain	1.0000
1:11824485:GGG:G	acceptor_gain	1.0000
1:11824485:GGGCT:G	acceptor_gain	1.0000
1:11824554:G:A	donor_loss	1.0000
1:11824555:T:G	donor_loss	1.0000

AlphaMissense

5698 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:11836008:T:A	V612D	1.000
1:11836047:T:C	L625P	1.000
1:11836077:T:A	V635E	1.000
1:11836080:T:A	V636D	1.000
1:11837432:G:A	G743D	1.000
1:11838635:T:C	L835P	1.000
1:11840149:G:A	G846R	1.000
1:11840149:G:C	G846R	1.000
1:11840149:G:T	G846W	1.000
1:11840150:G:A	G846E	1.000
1:11840150:G:T	G846V	1.000
1:11815846:A:C	S50R	0.999
1:11815848:T:A	S50R	0.999
1:11815848:T:G	S50R	0.999
1:11823755:G:C	G168R	0.999
1:11823756:G:A	G168D	0.999
1:11823756:G:T	G168V	0.999
1:11835975:C:A	A601D	0.999
1:11836035:T:C	L621P	0.999
1:11836050:G:C	R626P	0.999
1:11836074:C:G	P634R	0.999
1:11837431:G:C	G743R	0.999
1:11837432:G:T	G743V	0.999
1:11837453:T:C	L750P	0.999
1:11838539:T:A	V803D	0.999
1:11838572:T:A	V814D	0.999
1:11838641:T:A	V837E	0.999
1:11840171:T:C	L853P	0.999
1:11827098:A:C	R239S	0.998
1:11827098:A:T	R239S	0.998

dbSNP variants (sampled 300 via entrez): RS1000000481 (1:11813337 A>G), RS1000021406 (1:11833116 C>T), RS1000097776 (1:11825112 A>G), RS1000131218 (1:11817036 A>G), RS1000193112 (1:11824627 T>C), RS1000273042 (1:11808231 G>GTGTT), RS1000357647 (1:11829922 C>G,T), RS1000373283 (1:11816718 G>A), RS1000470710 (1:11818235 A>G), RS1000497581 (1:11833422 G>A), RS1000710717 (1:11817989 C>T), RS1000797486 (1:11834114 G>A), RS1001035089 (1:11812710 G>A,T), RS1001108743 (1:11807224 G>C,T), RS1001111101 (1:11824106 A>G)

Disease associations

OMIM: gene MIM:602726 | disease phenotypes: MIM:619173, MIM:225400

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities	Moderate	AD

Mondo (4): neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities (MONDO:0030947), breast ductal adenocarcinoma (MONDO:0005590), Ehlers-Danlos syndrome, kyphoscoliotic type 1 (MONDO:0016002), movement disorder (MONDO:0005395)

Orphanet (2): CLCN6-related childhood-onset progressive neurodegeneration-peripheral neuropathy syndrome (Orphanet:610573), Kyphoscoliotic Ehlers-Danlos syndrome due to lysyl hydroxylase 1 deficiency (Orphanet:1900)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000011	Neurogenic bladder
HP:0000219	Thin upper lip vermilion
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000364	Hearing abnormality
HP:0000639	Nystagmus
HP:0000646	Amblyopia
HP:0000763	Sensory neuropathy
HP:0000975	Hyperhidrosis
HP:0001137	Alternating esotropia
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0002093	Respiratory insufficiency
HP:0002353	EEG abnormality
HP:0002553	Highly arched eyebrow
HP:0003557	Increased variability in muscle fiber diameter
HP:0004370	Abnormality of temperature regulation
HP:0008936	Axial hypotonia
HP:0009886	Trichorrhexis nodosa
HP:0010602	Type 2 muscle fiber predominance
HP:0011471	Gastrostomy tube feeding in infancy
HP:0030680	Abnormal cardiovascular system morphology
HP:0100022	Abnormality of movement
HP:0100704	Cerebral visual impairment

GWAS associations

57 associations (top):

Study	Trait	p-value
GCST000395_2	Systolic blood pressure	2.000000e-13
GCST000957_2	Natriuretic peptide levels	4.000000e-16
GCST004602_3	Mean corpuscular volume	3.000000e-09
GCST004630_2	Mean corpuscular hemoglobin	2.000000e-11
GCST004635_2	Testicular germ cell tumor	2.000000e-10
GCST004923_1	Tuberculosis	1.000000e-11
GCST005196_178	Coronary artery disease	2.000000e-07
GCST005772_3	Diastolic blood pressure	3.000000e-06
GCST005777_1	Systolic blood pressure	7.000000e-06
GCST006166_45	Diastolic blood pressure x alcohol consumption interaction (2df test)	4.000000e-41
GCST006166_83	Diastolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-38
GCST006167_44	Mean arterial pressure x alcohol consumption interaction (2df test)	4.000000e-12
GCST006168_25	Pulse pressure x alcohol consumption interaction (2df test)	6.000000e-16
GCST006169_5	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	5.000000e-18
GCST006170_42	Systolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	6.000000e-20
GCST006170_8	Systolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	3.000000e-19
GCST006172_28	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	1.000000e-20
GCST006172_6	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	1.000000e-21
GCST006187_2	Diastolic blood pressure (cigarette smoking interaction)	9.000000e-40
GCST006187_3	Diastolic blood pressure (cigarette smoking interaction)	2.000000e-29
GCST006188_17	Systolic blood pressure (cigarette smoking interaction)	5.000000e-43
GCST006188_18	Systolic blood pressure (cigarette smoking interaction)	9.000000e-35
GCST006190_19	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	6.000000e-16
GCST006190_20	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	1.000000e-18
GCST006190_26	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-17
GCST006190_27	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	5.000000e-21
GCST006190_6	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	6.000000e-10
GCST006190_75	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	5.000000e-14
GCST006192_1	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	9.000000e-20
GCST006192_16	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-29

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004745	NT-proBNP measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0006336	diastolic blood pressure
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0005763	pulse pressure measurement
EFO:0006527	smoking status measurement
EFO:0009929	Beta blocking agent use measurement
EFO:0009928	Diuretic use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004517	arterial stiffness measurement
EFO:0004327	electrocardiography
EFO:0009188	Red cell distribution width
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D009069	Movement Disorders	C10.228.662
C536198	Ehlers-Danlos syndrome type 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1801133	Toxicity	3	antipsychotics	Schizophrenia
rs1801133	Toxicity	3	cisplatin;doxorubicin;methotrexate	Nephrotoxicity;Osteosarcoma

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5065	CLCN6, NPPA, NPPA-AS1	3	2.00	1	amlodipine;chlorthalidone
rs1801131	C1orf167, CLCN6, MTHFR	3	4.75	11	methotrexate;nitrous oxide;bevacizumab;carboplatin;cisplatin;cyanocobalamin;folic acid;pemetrexed;capecitabine;fluorouracil;leucovorin;oxaliplatin;clozapine;olanzapine;l-methylfolate;Vitamin B-complex;Incl. Combinations
rs1801133	CLCN6, MTHFR	2A	22.75	20	methotrexate;antipsychotics;nitrous oxide;capecitabine;fluorouracil;pravastatin;disulfiram;folic acid;vitamin b-complex;plain;benazepril;cisplatin;oxaliplatin;Platinum compounds
rs17367504	CLCN6, MTHFR		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — ClC family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
DIDS	Channel blocker	3.0	pIC50

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, affects expression, affects cotreatment, decreases expression	2
cupric chloride	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
Tretinoin	increases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression	2
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation, affects cotreatment, decreases methylation	1
beta-lapachone	decreases expression	1
2-bromopalmitate	increases abundance, increases palmitoylation, decreases reaction	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
cupric oxide	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
K 7174	increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
bisphenol S	increases methylation	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Amiodarone	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Curcumin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Manganese	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0AA	Ubigene HeLa CLCN6 KO	Cancer cell line	Female
CVCL_YA39	IDG-HEK293T-CLCN6-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

195 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT06710574	PHASE4	RECRUITING	Multimodal Image Technologies Investigate the Role and Mechanism of Probiotics in Improving RBD with Parkinson’s Disease
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT01838278	PHASE3	UNKNOWN	Effectiveness of Vojta Therapy in Motor Development of Preterm Children
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00001929	PHASE2	COMPLETED	Treatment of Parkinson’s Disease With Eliprodil
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00693472	PHASE2	TERMINATED	Study of Preladenant for the Treatment of Neuroleptic Induced Akathisia (Study P05145)
NCT01385592	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491529	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of Modified Release AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491932	PHASE2	COMPLETED	Open-label, Long-term Safety Extension Study of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT04536987	PHASE2	COMPLETED	Robot Therapy for Rehabilitation of Hand Movement After Stroke
NCT04912115	PHASE2	SUSPENDED	Randomized, Double-Blind, Active Placebo-Controlled Study of Ketamine to Treat Levodopa-Induced Dyskinesia
NCT05636852	PHASE2	TERMINATED	Altropane Dose for Imaging Patients With Suspected Parkinson’s Disease
NCT00001663	PHASE1	COMPLETED	Treatment of Cortical Myoclonus With Repetitive Transcranial Magnetic Stimulation
NCT02589340	PHASE1	TERMINATED	Buspirone, in Combination With Amantadine, for the Treatment of Levodopa-induced Dyskinesia
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT00036296	PHASE1/PHASE2	COMPLETED	Effects of Talampanel on Patients With Advanced Parkinson’s Disease
NCT00037167	PHASE1/PHASE2	COMPLETED	Effects of Exercise Poles on Older Adults During Exercise Walking
NCT03295786	PHASE1/PHASE2	COMPLETED	Clinical Study to Test the Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease
NCT03775538	PHASE1/PHASE2	COMPLETED	Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease. Extension to HP-CD-CL-2002 Clinical Study
NCT04228653	PHASE1/PHASE2	UNKNOWN	Long-Term Follow-up Safety After DDS Implantation With/Without CDNF Infusions
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT00500994	EARLY_PHASE1	COMPLETED	Neurobiology of Functional Movement Disorder and Non-Epileptic Seizures
NCT00001208	Not specified	RECRUITING	Botulinum Toxin for the Treatment of Involuntary Movement Disorders
NCT00001252	Not specified	RECRUITING	Human Movement Database