CLCN3

Protein identityUniProt · HPA

UniProt accession

P51790

Gene

CLCN3

Ensembl

ENSG00000109572

Chromosome

4

Canonical length

818 aa

Protein class

Disease related genes, Human disease related genes, Predicted intracellular proteins, Predicted membrane proteins

Subcellular location

Vesicles

Quaternary structure

Homodimer

OverviewNCBI Gene

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]

Canonical amino-acid sequenceUniProt

818 residues, UniProt reviewed canonical sequence.

>P51790|CLCN3
     1  MESEQLFHRG YYRNSYNSIT SASSDEELLD GAGVIMDFQT SEDDNLLDGD TAVGTHYTMT
    61  NGGSINSSTH LLDLLDEPIP GVGTYDDFHT IDWVREKCKD RERHRRINSK KKESAWEMTK
   121  SLYDAWSGWL VVTLTGLASG ALAGLIDIAA DWMTDLKEGI CLSALWYNHE QCCWGSNETT
   181  FEERDKCPQW KTWAELIIGQ AEGPGSYIMN YIMYIFWALS FAFLAVSLVK VFAPYACGSG
   241  IPEIKTILSG FIIRGYLGKW TLMIKTITLV LAVASGLSLG KEGPLVHVAC CCGNIFSYLF
   301  PKYSTNEAKK REVLSAASAA GVSVAFGAPI GGVLFSLEEV SYYFPLKTLW RSFFAALVAA
   361  FVLRSINPFG NSRLVLFYVE YHTPWYLFEL FPFILLGVFG GLWGAFFIRA NIAWCRRRKS
   421  TKFGKYPVLE VIIVAAITAV IAFPNPYTRL NTSELIKELF TDCGPLESSS LCDYRNDMNA
   481  SKIVDDIPDR PAGIGVYSAI WQLCLALIFK IIMTVFTFGI KVPSGLFIPS MAIGAIAGRI
   541  VGIAVEQLAY YHHDWFIFKE WCEVGADCIT PGLYAMVGAA ACLGGVTRMT VSLVVIVFEL
   601  TGGLEYIVPL MAAVMTSKWV GDAFGREGIY EAHIRLNGYP FLDAKEEFTH TTLAADVMRP
   661  RRNDPPLAVL TQDNMTVDDI ENMINETSYN GFPVIMSKES QRLVGFALRR DLTIAIESAR
   721  KKQEGIVGSS RVCFAQHTPS LPAESPRPLK LRSILDMSPF TVTDHTPMEI VVDIFRKLGL
   781  RQCLVTHNGR LLGIITKKDI LRHMAQTANQ DPASIMFN

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against CLCN3 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Cell surface

Secreted

No

Transmembrane segments

10

Mean surface accessibility (rSASA)

0.29

Highest tissue expression

66 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about CLCN3.

Disease | AllUniProt

Conditions CLCN3 is implicated in, by any mechanism.

• Neurodevelopmental disorder with hypotonia and brain abnormalities (NEDHYBA) MIM:619512
• Neurodevelopmental disorder with seizures and brain abnormalities (NEDSBA) MIM:619517

Disease | GeneticClinVar

16 pathogenic / likely-pathogenic of 202 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Neurodevelopmental disorder with hypotonia and brain abnormalities
• Neurodevelopmental delay
• Neurodevelopmental disorder
• Inborn genetic diseases
• Neurodevelopmental disorder with seizures and brain abnormalities

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.22

gnomAD pLI

1

gnomAD missense Z

4.37

DepMap mean gene effect

0.08

DepMap dependency class

none

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 3% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• adult locomotory behavior
• chloride transmembrane transport
• endosomal lumen acidification
• negative regulation of cell volume
• phagocytosis, engulfment
• photoreceptor cell maintenance
• positive regulation of reactive oxygen species biosynthetic process
• regulation of pH
• synaptic transmission, GABAergic
• synaptic transmission, glutamatergic
• synaptic vesicle lumen acidification

Molecular functions

• antiporter activity
• ATP binding
• chloride channel activity
• chloride:proton antiporter activity
• PDZ domain binding
• voltage-gated chloride channel activity
• volume-sensitive chloride channel activity

Cellular components

• axon terminus
• cell surface
• cytoplasmic vesicle
• early endosome
• early endosome membrane
• endosome membrane
• external side of plasma membrane
• GABA-ergic synapse
• glutamatergic synapse
• Golgi apparatus
• Golgi membrane
• late endosome
• late endosome membrane
• lysosomal membrane
• membrane
• phagocytic vesicle
• plasma membrane
• recycling endosome
• ruffle membrane
• secretory granule
• specific granule
• synaptic vesicle
• synaptic vesicle membrane
• vesicle membrane

Protein domainsUniProt · Pfam · InterPro

• CBS domain
• Chloride channel
• Chloride channel, core
• CBS domain superfamily
• CBS domain
• Voltage gated chloride channel
• H(+)/Cl(-) exchange transporter 3

KeywordsUniProt

• Antiport
• ATP-binding
• CBS domain
• Cell membrane
• Cell projection
• Chloride
• Endosome
• Epilepsy
• Glycoprotein
• Golgi apparatus
• Intellectual disability
• Ion transport
• Lysosome
• Membrane
• Nucleotide-binding
• Repeat
• Transmembrane
• Transmembrane helix
• Transport

InteractionsUniProt · HPA

Protein binding partners of CLCN3 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• GOPC
• PDZK1
• NHERF1