CLCN4

Summary

CLCN4 (Cl-/H+ antiporter 4, HGNC:2022) is a protein-coding gene on chromosome Xp22.2, encoding H(+)/Cl(-) exchange transporter 4 (P51793). Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.

The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. Chloride channel 4 has an evolutionary conserved CpG island and is conserved in both mouse and hamster. This gene is mapped in close proximity to APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism type I), which are both located on the human X chromosome at band p22.3. The physiological role of chloride channel 4 remains unknown but may contribute to the pathogenesis of neuronal disorders. Alternate splicing results in two transcript variants that encode different proteins.

Source: NCBI Gene 1183 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 853 total — 38 pathogenic, 30 likely-pathogenic
• Phenotypes (HPO): 57
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001830

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2022
Approved symbol	CLCN4
Name	Cl-/H+ antiporter 4
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Aliases	CLC4, ClC-4
Ensembl gene	ENSG00000073464
Ensembl biotype	protein_coding
OMIM	302910
Entrez	1183

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000380829, ENST00000380833, ENST00000421085, ENST00000454850, ENST00000674669, ENST00000674959, ENST00000675144, ENST00000675769, ENST00000888017, ENST00000888018, ENST00000888019, ENST00000888020, ENST00000888021, ENST00000947381, ENST00000947382, ENST00000947383

RefSeq mRNA: 2 — MANE Select: NM_001830 NM_001256944, NM_001830

CCDS: CCDS14137, CCDS59159

Canonical transcript exons

ENST00000380833 — 13 exons

Exon	Start	End
ENSE00001293638	10158289	10158551
ENSE00001486458	10233494	10237660
ENSE00001486498	10185022	10185176
ENSE00001486501	10156975	10157100
ENSE00001615425	10213681	10214079
ENSE00001637054	10212467	10212653
ENSE00001690214	10220661	10220877
ENSE00001717438	10206358	10206564
ENSE00001739626	10208045	10208590
ENSE00001795104	10197939	10198061
ENSE00001802970	10206696	10206776
ENSE00002306386	10187515	10187614
ENSE00003644653	10194911	10195098

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 96.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.7038 / max 186.5970, expressed in 926 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195477	3.9972	438
195474	1.3456	623
195475	0.3455	160
195476	0.0154	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	96.89	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.26	gold quality
postcentral gyrus	UBERON:0002581	95.63	gold quality
orbitofrontal cortex	UBERON:0004167	95.35	gold quality
biceps brachii	UBERON:0001507	95.17	gold quality
parietal lobe	UBERON:0001872	95.08	gold quality
corpus epididymis	UBERON:0004359	94.84	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.80	gold quality
endothelial cell	CL:0000115	94.77	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.77	gold quality
superior frontal gyrus	UBERON:0002661	94.64	gold quality
pigmented layer of retina	UBERON:0001782	94.60	gold quality
pons	UBERON:0000988	94.20	gold quality
entorhinal cortex	UBERON:0002728	93.97	gold quality
cortical plate	UBERON:0005343	93.50	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.48	gold quality
gluteal muscle	UBERON:0002000	93.35	gold quality
primary visual cortex	UBERON:0002436	93.05	gold quality
secondary oocyte	CL:0000655	93.00	gold quality
vastus lateralis	UBERON:0001379	92.54	gold quality
substantia nigra pars compacta	UBERON:0001965	92.43	gold quality
occipital lobe	UBERON:0002021	92.40	gold quality
globus pallidus	UBERON:0001875	92.30	gold quality
cerebellar vermis	UBERON:0004720	92.27	gold quality
lateral globus pallidus	UBERON:0002476	92.24	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.07	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.05	gold quality
medial globus pallidus	UBERON:0002477	92.02	gold quality
inferior olivary complex	UBERON:0002127	91.86	gold quality
superior vestibular nucleus	UBERON:0007227	91.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.33

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

187 targeting CLCN4, 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-3163	100.00	77.23	8605
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-557	99.96	70.01	1640
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-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 16)

• Vesicle acidification, exocytosis, endocytosis, and secretory pathway. (PMID:10564087)
• absence of learning difficulties in a hyperactive boy with a terminal Xp deletion encompassing the MRX49 locus (PMID:11474655)
• ClC-4 is an intracellular chloride channel that stimulates copper incorporation into ceruloplasmin, probably by improving the efficiency of the ATP7B copper pump. (PMID:15057754)
• coupled Cl-/H+ transport of ClC-4 and ClC-5 is of significant magnitude in vivo (PMID:16034421)
• crystal structure: CLIC4 appears to be able to form a redox-regulated ion channel in the absence of any partner proteins (PMID:16176272)
• A stretch of amino acids, residues 14-63, at the N-terminus constitutes a novel motif both necessary and sufficient for targeting hClC-4 and other membrane proteins to the endoplasmic reticulum. (PMID:17023393)
• The proposed mechanism results in anion-dependent conversion of ClC-type exchanger into an anion channel with typical attributes of ClC anion channels. (PMID:19364886)
• Studies showed that three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent’s disease. (PMID:19546591)
• CLCN4 is a novel driver of colon cancer progression. (PMID:20087350)
• the voltage dependence of uncoupled ClC-4 by protons and anions (PMID:21354396)
• This study performed whole exome sequencing demonistrated that the true de novo variants represent mutations in genes (KCNH5, CLCN4, and ARHGEF15) not previously associated with epilepsies in humans. (PMID:23647072)
• We report 10 additional families with nine novel CLCN4 variants, extend the molecular spectrum to include splice site variants and single-exon deletions, suggest genotype-phenotype correlation, and present detailed clinical phenotypic information about CLCN4-related disorder in 29 hemizygous males and 23 heterozygous females from 16 families. (PMID:27550844)
• Unique oligomerization properties of ClC-4 permit regulated targeting of ClC-4 to various endosomal compartment systems via expression of different ClC-3 splice variants. (PMID:28972156)
• The molecular and phenotypic spectrum of CLCN4-related epilepsy. (PMID:33951195)
• Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition. (PMID:36385166)
• Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy. (PMID:38578438)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	clcn4	ENSDARG00000035808
mus_musculus	Clcn4	ENSMUSG00000000605
rattus_norvegicus	Clcn4	ENSRNOG00000003533
drosophila_melanogaster	ClC-c	FBGN0036566
caenorhabditis_elegans		WBGENE00000532

Paralogs (8): CLCN6 (ENSG00000011021), CLCN7 (ENSG00000103249), CLCN3 (ENSG00000109572), CLCN2 (ENSG00000114859), CLCN5 (ENSG00000171365), CLCNKB (ENSG00000184908), CLCNKA (ENSG00000186510), CLCN1 (ENSG00000188037)

Protein

Protein identifiers

H(+)/Cl(-) exchange transporter 4 — P51793 (reviewed: P51793)

Alternative names: Chloride channel protein 4, Chloride transporter ClC-4

All UniProt accessions (6): P51793, A0A6Q8PF24, A0A6Q8PG54, A0A7I2Y1J6, E9PFB5, G3XAG5

UniProt curated annotations — full annotation on UniProt →

Function. Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons. 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.

Subunit / interactions. Monomer. Forms heterodimers with CLCN3.

Subcellular location. Early endosome membrane. Late endosome membrane. Endoplasmic reticulum membrane. Lysosome membrane. Recycling endosome membrane.

Tissue specificity. Abundant in skeletal muscle and also detectable in brain and heart.

Disease relevance. Raynaud-Claes syndrome (MRXSRC) [MIM:300114] An X-linked syndrome characterized by borderline to severe intellectual disability and impaired language development. Additional features include behavioral problems, psychiatric disorders, seizures, progressive ataxia, brain abnormalities, and facial dysmorphisms. 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-4/CLCN4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P51793-1	1	yes
P51793-2	2

RefSeq proteins (2): NP_001243873, NP_001821* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000644	CBS_dom	Domain
IPR001807	ClC	Family
IPR002246	Cl_channel-4	Family
IPR014743	Cl-channel_core	Homologous_superfamily
IPR046342	CBS_dom_sf	Homologous_superfamily

Pfam: PF00571, PF00654

UniProt features (52 total): sequence variant 12, transmembrane region 10, intramembrane region 6, binding site 6, short sequence motif 3, sequence conflict 3, topological domain 2, domain 2, region of interest 2, site 2, mutagenesis site 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51793-F1	84.66	0.46

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): 224 (mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking h(+) and cl(-) transport); 281 (mediates proton transfer from the protein to the inner aqueous phase)

Ligand- & substrate-binding residues (6): 181; 469; 572; 610; 631–633; 738–741

Mutagenesis-validated functional residues (2):

Position	Phenotype
224	restores chloride translocation, but not proton transport; when associated with a-281.
281	abolishes translocation of protons and chloride ions.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 341 (showing top): GOCC_VACUOLAR_MEMBRANE, PAL_PRMT5_TARGETS_UP, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, GOBP_CILIUM_ORGANIZATION, CORRE_MULTIPLE_MYELOMA_UP, GOBP_ORGANELLE_ASSEMBLY, CREB_Q2_01, MORF_THPO, MODULE_113, GOBP_CELL_PROJECTION_ORGANIZATION, YANAGIHARA_ESX1_TARGETS, VANTVEER_BREAST_CANCER_ESR1_DN, CONCANNON_APOPTOSIS_BY_EPOXOMICIN_DN, MILI_PSEUDOPODIA_CHEMOTAXIS_DN

GO Biological Process (6): chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), non-motile cilium assembly (GO:1905515), monoatomic ion transport (GO:0006811), transmembrane transport (GO:0055085), chloride transmembrane transport (GO:1902476)

GO Molecular Function (7): voltage-gated chloride channel activity (GO:0005247), chloride channel activity (GO:0005254), ATP binding (GO:0005524), antiporter activity (GO:0015297), nucleotide binding (GO:0000166), protein binding (GO:0005515), chloride transmembrane transporter activity (GO:0015108)

GO Cellular Component (16): lysosomal membrane (GO:0005765), early endosome (GO:0005769), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), endosome membrane (GO:0010008), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), ciliary base (GO:0097546), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome	3
endomembrane system	3
endosome membrane	3
transport	2
cytoplasm	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
monoatomic anion transport	1
inorganic anion transport	1
monoatomic ion transport	1
transmembrane transport	1
cilium assembly	1
cellular process	1
chloride transport	1
monoatomic anion transmembrane transport	1
chloride channel activity	1
voltage-gated monoatomic anion channel activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter 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
binding	1
monoatomic anion transmembrane transporter activity	1
chloride transmembrane transport	1
lysosome	1
lytic vacuole membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
exocytic vesicle	1
presynapse	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
early endosome	1
late endosome	1

Protein interactions and networks

STRING

935 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCN4	AMELX	Q99217	709
CLCN4	CLIC4	Q9Y696	683
CLCN4	CLIC1	O00299	672
CLCN4	MID1	O15344	667
CLCN4	ASMT	P46597	649
CLCN4	CLCN5	P51795	583
CLCN4	SLC25A6	P12236	582
CLCN4	OSTM1	Q86WC4	577
CLCN4	EPRS1	P07814	550
CLCN4	STS	P08842	496
CLCN4	TSNARE1	Q96NA8	496
CLCN4	ARHGEF1	Q92888	494
CLCN4	BSND	Q8WZ55	476
CLCN4	DNAJC5	Q9H3Z4	444
CLCN4	CSF2RA	P15509	437

IntAct

8 interactions, top by confidence:

A	B	Type	Score
CLCN4	ABHD5	psi-mi:“MI:0915”(physical association)	0.560
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
TMEM9B	NBAS	psi-mi:“MI:0914”(association)	0.350
TMEM9B	FANCG	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): CLCN4 (Affinity Capture-RNA), CLCN4 (Affinity Capture-MS), CLCN4 (Affinity Capture-MS), MTAP (Cross-Linking-MS (XL-MS)), SLC12A4 (Co-fractionation), CLCN4 (Co-fractionation), CLCN4 (Co-fractionation), CLCN5 (Co-fractionation), LNPEP (Co-fractionation), LYSMD4 (Co-fractionation), MCOLN1 (Co-fractionation), PKN2 (Co-fractionation), PRKAR2A (Co-fractionation), SLC1A1 (Co-fractionation), SLC1A3 (Co-fractionation)

ESM2 similar proteins: A3QM97, O18894, O60159, P0C197, P21564, P35522, P37020, P51790, P51791, P51792, P51793, P51794, P51795, P51796, P60300, P92941, P92942, Q09573, Q28677, Q28E01, Q2UVJ5, Q54AX6, Q5RBK4, Q5RDJ7, Q5RK27, Q61418, Q63632, Q63633, Q657W3, Q6NV12, Q6Z0E2, Q75JF3, Q86AZ6, Q91V14, Q924N4, Q95L97, Q96282, Q99P66, Q9BMK9, Q9ES44

Diamond homologs: A7FHW4, A7ZM51, A8A0D3, A8AGW0, B1IQZ8, B1LEU5, B1XF57, B2U1Q2, B5FHR3, B5Z428, B7L5E4, B7LZY4, B7MV39, B7NB42, B7NUP7, B7URT1, C4ZY54, P51793, P59638, P76175, Q61418, Q8FHC1, Q8X794, Q8XTT4, Q8Z6Y0, Q8ZEB3, Q8ZPK5, Q9AGD5, O18894, O60159, P0C197, P35525, P37020, P51788, P51789, P51790, P51791, P51792, P51794, P51795

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CLCN4	“down-regulates quantity”	chloride	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	30
Uncertain significance	307
Likely benign	233
Benign	72

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100781	NM_001830.4(CLCN4):c.1630G>A (p.Gly544Arg)	Pathogenic
1069029	NM_001830.4(CLCN4):c.497dup (p.Leu166fs)	Pathogenic
1070891	NM_001830.4(CLCN4):c.2191G>A (p.Gly731Arg)	Pathogenic
1072902	NM_001830.4(CLCN4):c.2192+1G>T	Pathogenic
1076936	NM_001830.4(CLCN4):c.1490G>A (p.Trp497Ter)	Pathogenic
1164025	NM_001830.4(CLCN4):c.875G>A (p.Trp292Ter)	Pathogenic
1421100	NC_000023.10:g.(?10153073)(10180703_?)del	Pathogenic
1439217	NM_001830.4(CLCN4):c.1712_1715dup (p.Glu573fs)	Pathogenic
1679299	NM_001830.4(CLCN4):c.112G>T (p.Glu38Ter)	Pathogenic
1691411	NM_001830.4(CLCN4):c.925_928del (p.Asn309fs)	Pathogenic
209111	NM_001830.4(CLCN4):c.635T>G (p.Val212Gly)	Pathogenic
209112	NM_001830.4(CLCN4):c.662T>C (p.Leu221Pro)	Pathogenic
209113	NM_001830.4(CLCN4):c.1601C>T (p.Ser534Leu)	Pathogenic
209114	GRCh37/hg19 Xp22.2(chrX:10187807-10189796)	Pathogenic
209115	NM_001830.4(CLCN4):c.1664C>T (p.Ala555Val)	Pathogenic
209116	NM_001830.4(CLCN4):c.2152C>T (p.Arg718Trp)	Pathogenic
209117	NM_001830.4(CLCN4):c.823G>A (p.Val275Met)	Pathogenic
209118	NM_001830.4(CLCN4):c.1876dup (p.Ile626fs)	Pathogenic
224917	NM_001830.4(CLCN4):c.1630G>C (p.Gly544Arg)	Pathogenic
253112	NM_001830.4(CLCN4):c.43_55del (p.Asp15fs)	Pathogenic
253113	NM_001830.4(CLCN4):c.2191G>C (p.Gly731Arg)	Pathogenic
253115	NM_001830.4(CLCN4):c.661C>G (p.Leu221Val)	Pathogenic
253116	NM_001830.4(CLCN4):c.1606G>A (p.Val536Met)	Pathogenic
2705896	NM_001830.4(CLCN4):c.1174C>T (p.Gln392Ter)	Pathogenic
2760815	NM_001830.4(CLCN4):c.1068G>A (p.Trp356Ter)	Pathogenic
2849855	NM_001830.4(CLCN4):c.1716C>A (p.Tyr572Ter)	Pathogenic
3024251	NM_001830.4(CLCN4):c.1631G>A (p.Gly544Glu)	Pathogenic
3235813	NM_001830.4(CLCN4):c.980G>A (p.Trp327Ter)	Pathogenic
3648299	NM_001830.4(CLCN4):c.1517_1527dup (p.Cys510fs)	Pathogenic
3651445	NM_001830.4(CLCN4):c.586del (p.Arg196fs)	Pathogenic

SpliceAI

2049 predictions. Top by Δscore:

Variant	Effect	Δscore
X:10158273:T:G	acceptor_gain	1.0000
X:10185017:CCCA:C	acceptor_loss	1.0000
X:10185018:CCA:C	acceptor_loss	1.0000
X:10185020:A:AT	acceptor_loss	1.0000
X:10185021:G:GC	acceptor_loss	1.0000
X:10185021:GGT:G	acceptor_gain	1.0000
X:10185021:GGTGT:G	acceptor_gain	1.0000
X:10185172:GGAAG:G	donor_gain	1.0000
X:10185173:GAAG:G	donor_gain	1.0000
X:10185173:GAAGG:G	donor_gain	1.0000
X:10185174:A:T	donor_gain	1.0000
X:10185174:AAGG:A	donor_loss	1.0000
X:10185176:GGTA:G	donor_loss	1.0000
X:10185177:G:GG	donor_gain	1.0000
X:10185177:GTAG:G	donor_loss	1.0000
X:10195096:GAG:G	donor_gain	1.0000
X:10197937:AG:A	acceptor_gain	1.0000
X:10197938:GG:G	acceptor_gain	1.0000
X:10198059:GAG:G	donor_gain	1.0000
X:10198059:GAGGT:G	donor_loss	1.0000
X:10198060:AGGT:A	donor_loss	1.0000
X:10198061:GGT:G	donor_loss	1.0000
X:10198062:G:A	donor_loss	1.0000
X:10198063:T:A	donor_loss	1.0000
X:10206692:GTAG:G	acceptor_loss	1.0000
X:10206772:AAGAG:A	donor_loss	1.0000
X:10206774:GAG:G	donor_gain	1.0000
X:10206774:GAGG:G	donor_loss	1.0000
X:10206775:AGGT:A	donor_loss	1.0000
X:10206777:GT:G	donor_loss	1.0000

AlphaMissense

4983 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:10185135:T:A	W35R	1.000
X:10185135:T:C	W35R	1.000
X:10185137:G:C	W35C	1.000
X:10185137:G:T	W35C	1.000
X:10195062:G:C	W132C	1.000
X:10195062:G:T	W132C	1.000
X:10198050:G:C	G182R	1.000
X:10198051:G:A	G182D	1.000
X:10206363:G:C	K187N	1.000
X:10206363:G:T	K187N	1.000
X:10206376:G:C	G192R	1.000
X:10206377:G:A	G192D	1.000
X:10206377:G:T	G192V	1.000
X:10206379:T:C	F193L	1.000
X:10206380:T:C	F193S	1.000
X:10206381:T:A	F193L	1.000
X:10206381:T:G	F193L	1.000
X:10206560:G:C	R253P	1.000
X:10206715:C:A	A261D	1.000
X:10206720:G:A	G263R	1.000
X:10206720:G:C	G263R	1.000
X:10206721:G:A	G263E	1.000
X:10206735:T:C	F268L	1.000
X:10206737:T:A	F268L	1.000
X:10206737:T:G	F268L	1.000
X:10206750:G:A	G273R	1.000
X:10206750:G:C	G273R	1.000
X:10206751:G:A	G273E	1.000
X:10206753:G:C	G274R	1.000
X:10206754:G:A	G274D	1.000

dbSNP variants (sampled 300 via entrez): RS1000063884 (X:10229082 G>A), RS1000214527 (X:10238041 C>G), RS1000316336 (X:10166196 C>A), RS1000325874 (X:10187439 G>A), RS1000330284 (X:10229403 A>G,T), RS1000478781 (X:10196761 G>A), RS1000633486 (X:10205022 G>A), RS1000670 (X:10213295 C>A,T), RS1000708965 (X:10222616 G>A), RS1000721856 (X:10230027 A>T), RS1000748138 (X:10197213 A>G), RS1000752024 (X:10229482 T>A), RS1000813985 (X:10187665 C>T), RS1000823930 (X:10187101 AAGG>A), RS1000835826 (X:10164188 T>C)

Disease associations

OMIM: gene MIM:302910 | disease phenotypes: MIM:300114, MIM:300433, MIM:181500, MIM:309530

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 49	Strong	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Definitive	XL

Mondo (7): intellectual disability, X-linked 49 (MONDO:0010250), neurodevelopmental disorder (MONDO:0700092), intellectual disability, X-linked 81 (MONDO:0010324), intellectual disability (MONDO:0001071), schizophrenia (MONDO:0005090), microcephaly (MONDO:0001149), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (5): CLCN4-related X-linked intellectual disability syndrome (Orphanet:485350), X-linked non-syndromic intellectual disability (Orphanet:777), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000752	Hyperactivity
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001423	X-linked dominant inheritance
HP:0001763	Pes planus
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002061	Lower limb spasticity

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003124_29	Mild influenza (H1N1) infection	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001488	influenza A (H1N1)

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
C564515	Mental Retardation, X-Linked 81 (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — ClC family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
Zn2+	Channel blocker	4.3	pIC50
Cd2+	Channel blocker	4.2	pIC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	6
(+)-JQ1 compound	decreases expression	2
Estradiol	affects cotreatment, increases expression	2
Nickel	decreases expression	2
aristolochic acid I	increases expression	1
ethylbenzene	affects cotreatment, decreases expression, increases methylation	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
terbufos	decreases methylation	1
trichostatin A	increases expression	1
sulforaphane	increases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	increases expression, affects binding	1
Sunitinib	increases expression	1
Air Pollutants, Occupational	increases methylation, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Doxorubicin	decreases expression	1
Fonofos	decreases methylation	1
Lead	affects expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Parathion	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice