CLCN7

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005254 chloride channel activity	IBA GO_REF:0000033	MODIFY	Summary: ClC-7 is an electrogenic 2Cl(-)/1H(+) antiporter, not a passive chloride channel. The "chloride channel activity" term reflects historical CLC family naming but is mechanistically imprecise for ClC-7. Reason: The verified molecular function of ClC-7 is coupled Cl(-)/H(+) exchange, directly demonstrated electrophysiologically with a measured 2Cl(-)/1H(+) stoichiometry. A more accurate term, chloride:proton antiporter activity (GO:0062158), is already present in GOA and should replace the generic channel term. Proposed replacements: chloride:proton antiporter activity Supporting Evidence: PMID:21527911 Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry. PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0005765 lysosomal membrane	IBA GO_REF:0000033	ACCEPT	Summary: ClC-7 is active in the lysosomal membrane, where it performs Cl(-)/H(+) exchange. This localization is strongly supported by multiple experimental studies. Reason: Lysosomal membrane is the core site of ClC-7 action and is corroborated by direct experimental localization and functional studies. Supporting Evidence: PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0005770 late endosome	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: ClC-7/OSTM1 resides in the late endosomal/lysosomal system, so late endosome localization is plausible but is a less central site than the lysosome. Reason: Late endosomal localization is consistent with ClC-7 being an endolysosomal transporter, but the dominant and functionally characterized compartment is the lysosome; this phylogenetically inferred late-endosome term is retained as non-core. Supporting Evidence: PMID:32851177 CLC-7 functions as an electrogenic antiporter that mainly resides in lysosomes and osteoclast ruffled membranes.
GO:0030321 transepithelial chloride transport	IBA GO_REF:0000033	REMOVE	Summary: ClC-7 is an intracellular endolysosomal Cl(-)/H(+) antiporter, not a plasma-membrane transporter mediating transepithelial chloride movement. Reason: Transepithelial chloride transport implies vectorial transport across an epithelial cell layer at the plasma membrane. ClC-7 acts on intracellular organelle membranes (lysosome, osteoclast ruffled border); this term is an over-annotation transferred phylogenetically and from a ComplexPortal complex annotation. An OpenScientist run traced the annotation to a ComplexPortal family-level introductory sentence (not specific to ClC-7) that was then propagated by PANTHER IBA to ~1,198 ortholog annotations, and confirmed via sorting-signal analysis that ClC-7 carries N-terminal dileucine and acidic-cluster lysosomal targeting motifs (absent from the plasma-membrane paralogs CLCNKA/CLCNKB) and never participates in transepithelial transport, so the term should be removed rather than merely flagged. Supporting Evidence: PMID:32851177 CLC-7 functions as an electrogenic antiporter that mainly resides in lysosomes and osteoclast ruffled membranes. file:human/CLCN7/CLCN7-hypotheses/topology-transepithelial-overannotation/openscientist.md a PANTHER IBA (Inferred by Biological Aspect of Ancestor) annotation that propagated this error to CLCN7 orthologs across approximately 1,198 annotations in many species. file:human/CLCN7/CLCN7-hypotheses/topology-transepithelial-overannotation/openscientist.md CLC-7 contains N-terminal dileucine and acidic cluster sorting motifs that actively target it to lysosomes
GO:0034707 chloride channel complex	IBA GO_REF:0000033	ACCEPT	Summary: ClC-7 is part of an obligate heteromeric complex with the beta-subunit OSTM1. This term captures that real CLCN7-OSTM1 complex (the "channel" label reflects family naming convention). Reason: The CLCN7-OSTM1 complex is well established structurally and functionally (ComplexPortal CPX-6321), and OSTM1 is required for ClC-7 stability and activity. The term name uses "channel" by family convention, but the complex assignment is correct. Supporting Evidence: PMID:21527911 ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity. PMID:32851177 the highly glycosylated Ostm1 functions like a lid positioned above CLC-7 and interacts extensively with CLC-7 within the membrane.
GO:0062158 chloride:proton antiporter activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the accurate core molecular function of ClC-7, matching the experimentally measured 2Cl(-)/1H(+) exchange. Reason: Direct electrophysiology established a 2Cl(-)/1H(+)-exchange stoichiometry, and ClC-7 mediates the major lysosomal Cl(-)/H(+) antiport. This term precisely describes the verified activity. Supporting Evidence: PMID:21527911 Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry. PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:1902476 chloride transmembrane transport	IBA GO_REF:0000033	ACCEPT	Summary: ClC-7 mediates transmembrane chloride movement as part of its Cl(-)/H(+) exchange across the lysosomal membrane. Reason: Chloride transmembrane transport is a correct biological-process description of ClC-7 antiporter activity and is well supported experimentally. Supporting Evidence: PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0005254 chloride channel activity	IEA GO_REF:0000117	MODIFY	Summary: Same imprecise channel term as the IBA annotation, here from an ARBA machine-learning model. ClC-7 is an antiporter. Reason: ClC-7 mediates coupled 2Cl(-)/1H(+) exchange rather than passive channel conduction; chloride:proton antiporter activity (GO:0062158) is the accurate replacement. Proposed replacements: chloride:proton antiporter activity Supporting Evidence: PMID:21527911 Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry.
GO:0005765 lysosomal membrane	IEA GO_REF:0000044	ACCEPT	Summary: Lysosomal membrane localization, here from UniProt subcellular-location mapping; corroborated by experimental evidence. Reason: Lysosomal membrane is the core localization of ClC-7 and is independently supported by experimental studies. Supporting Evidence: PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0006821 chloride transport	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Generic chloride transport, an InterPro2GO transfer. Correct but less specific than chloride transmembrane transport / antiporter activity. Reason: This term is a high-level parent consistent with ClC-7 function but is superseded by the more specific chloride transmembrane transport and chloride:proton antiporter terms already annotated. Supporting Evidence: PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0015108 chloride transmembrane transporter activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Generic chloride transmembrane transporter activity from InterPro2GO. This is the correct parent of the antiporter activity but does not capture the coupled exchange mechanism. Reason: Correct but generic; the specific chloride:proton antiporter activity (GO:0062158) is the informative molecular-function term. Retained as non-core. Supporting Evidence: PMID:21527911 Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry.
GO:0016020 membrane	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Uninformative generic membrane localization from InterPro2GO. Reason: "membrane" is an uninformatively broad cellular-component term; the specific lysosomal membrane localization is already captured by experimental annotations.
GO:0055085 transmembrane transport	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Generic transmembrane transport from InterPro2GO. Reason: A high-level parent of the specific chloride transmembrane transport term; consistent with ClC-7 function but uninformative on its own. Retained as non-core.
GO:0062158 chloride:proton antiporter activity	IEA GO_REF:0000002	ACCEPT	Summary: Accurate antiporter molecular function, here from InterPro2GO; matches the experimentally verified activity. Reason: This is the verified core molecular function and is independently supported by direct electrophysiological measurement of 2Cl(-)/1H(+) exchange. Supporting Evidence: PMID:21527911 Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	ACCEPT	Summary: Proton transmembrane transport, inferred logically from the antiporter activity. ClC-7 does move protons as part of its coupled exchange. Reason: Proton movement is an intrinsic half of the 2Cl(-)/1H(+) exchange and is directly supported by the measured stoichiometry and the role in lysosomal acidification. Supporting Evidence: PMID:21527911 Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a high-throughput binary interactome screen; uninformative about ClC-7 function. Reason: GO:0005515 protein binding conveys no specific molecular function. The interactions reported in this large-scale screen are not the functionally defining OSTM1 partnership and do not warrant a specific term.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a neurodegenerative-disease interactome map; uninformative. Reason: GO:0005515 protein binding is uninformative and does not capture a specific molecular function for ClC-7.
GO:0005515 protein binding	IPI PMID:32851177 Molecular insights into the human CLC-7/Ostm1 transporter.	MARK AS OVER ANNOTATED	Summary: This IPI is to OSTM1 (Q86WC4), the functionally essential beta-subunit; however, as bare "protein binding" it is uninformative, and the OSTM1 partnership is better captured by the chloride channel complex term. Reason: Although the underlying OSTM1 interaction is biologically central, the generic GO:0005515 term adds nothing beyond the CLCN7-OSTM1 complex annotation (GO:0034707). Use the complex term rather than bare protein binding. Supporting Evidence: PMID:32851177 the highly glycosylated Ostm1 functions like a lid positioned above CLC-7 and interacts extensively with CLC-7 within the membrane.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" (interaction with OSTM1, Q86WC4) from a proteome-scale network study; uninformative as a generic term. Reason: The generic GO:0005515 term is uninformative; the OSTM1 partnership it reflects is already captured by the chloride channel complex annotation.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from the OpenCell endogenous-tagging interactome; uninformative. Reason: GO:0005515 protein binding conveys no specific molecular function for ClC-7.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" (OSTM1, Q86WC4) from a multimodal cell-map study; uninformative as a generic term. Reason: The generic GO:0005515 term adds nothing beyond the already-annotated CLCN7-OSTM1 complex term.
GO:0005515 protein binding	IPI PMID:40355756 The solute carrier superfamily interactome.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a solute-carrier superfamily interactome; uninformative. Reason: GO:0005515 protein binding conveys no specific molecular function and should not be retained as a core annotation.
GO:0009268 response to pH	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Response to pH, transferred electronically from a rat ortholog. There is no direct human experimental support, although ClC-7 does contribute to lysosomal pH regulation. Reason: The term is plausible given ClC-7's role in luminal acidification, but it rests on automated ortholog transfer without direct human evidence and is peripheral to the core transporter function. Retained as non-core. Supporting Evidence: PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0005765 lysosomal membrane	EXP PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeati...	ACCEPT	Summary: Direct experimental demonstration that ClC-7 localizes to and functions at the lysosomal membrane. Reason: This is the strongest, experimentally grounded evidence for ClC-7's core lysosomal membrane localization. Supporting Evidence: PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0005765 lysosomal membrane	IDA PMID:21527911 ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and r...	ACCEPT	Summary: Direct localization of the ClC-7/OSTM1 complex to the lysosomal membrane. Reason: Experimentally supported core localization; the complex requires OSTM1 for proper expression and trafficking. Supporting Evidence: PMID:21527911 ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity.
GO:0030321 transepithelial chloride transport	IDA PMID:32851177 Molecular insights into the human CLC-7/Ostm1 transporter.	MARK AS OVER ANNOTATED	Summary: ClC-7 is an intracellular endolysosomal antiporter, not a plasma-membrane mediator of transepithelial chloride flux. This ComplexPortal-derived term mislabels the biological process. Reason: The cited structural study localizes CLC-7 to lysosomes and osteoclast ruffled membranes, not to polarized epithelial plasma membranes mediating transepithelial transport. The term is an over-annotation. Supporting Evidence: PMID:32851177 CLC-7 functions as an electrogenic antiporter that mainly resides in lysosomes and osteoclast ruffled membranes.
GO:0034707 chloride channel complex	IPI PMID:32851177 Molecular insights into the human CLC-7/Ostm1 transporter.	ACCEPT	Summary: ClC-7 is part of the obligate CLCN7-OSTM1 heteromeric complex, directly visualized by cryo-EM. Reason: The cryo-EM structure of the human CLC-7/OSTM1 complex directly establishes this complex membership; OSTM1 forms a glycosylated lid over CLC-7. Supporting Evidence: PMID:32851177 the highly glycosylated Ostm1 functions like a lid positioned above CLC-7 and interacts extensively with CLC-7 within the membrane.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Generic membrane localization from a high-throughput NK-cell membrane proteome; uninformative. Reason: "membrane" is uninformatively broad; the specific lysosomal membrane localization is established by direct experimental evidence.
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: Lysosomal membrane localization from a lysosomal-proteome mass-spectrometry study, corroborating the core localization. Reason: Detection in the lysosomal membrane proteome supports the experimentally established core localization of ClC-7. Supporting Evidence: PMID:17897319 Integral and associated lysosomal membrane proteins.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-2730959	ACCEPT	Summary: Lysosomal membrane localization asserted in the Reactome reaction for CLCN7:OSTM1 Cl-/H+ exchange. Reason: Consistent with the experimentally established core lysosomal membrane localization and the Cl(-)/H(+) exchange reaction catalyzed there. Supporting Evidence: PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0005254 chloride channel activity	TAS PMID:8543009 ClC-6 and ClC-7 are two novel broadly expressed members of t...	MODIFY	Summary: This 1995 cloning paper named ClC-7 within the CLC "chloride channel family" but reported it could not be expressed as a chloride channel; ClC-7 is now known to be a 2Cl(-)/1H(+) antiporter. Reason: The chloride channel designation reflects family naming, and the cited paper itself found no channel activity in heterologous expression. The verified function is coupled Cl(-)/H(+) exchange (GO:0062158). Proposed replacements: chloride:proton antiporter activity Supporting Evidence: PMID:18449189 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.
GO:0080025 phosphatidylinositol-3,5-bisphosphate binding	IDA PMID:35670560 Tonic inhibition of the chloride/proton antiporter ClC-7 by ...	NEW	Summary: ClC-7 transport is tonically inhibited by the lysosome-specific signaling lipid PI(3,5)P2, which binds a pocket at the transmembrane-cytosolic interface; relief of inhibition activates the antiporter and modulates lysosomal acidification [PMID:35670560]. Gain-of-function HOD variants Y715C and K285T lie in this lipid-binding site and reduce PI(3,5)P2 inhibition [PMID:38838776]. This regulatory molecular function is well established experimentally but is not currently present in GOA. Supporting Evidence: PMID:35670560 PI(3,5)P2 inhibits ClC-7-mediated currents. PMID:38838776 K285 is located in a suggested binding site for PI(3,5)P2 in the cytoplasmic portion of ClC-7

Gene Description

Existing Annotations Review

Core Functions

ClC-7 functions as an electrogenic 2Cl(-)/1H(+) antiporter in the lysosomal membrane, exchanging two chloride ions for one proton and thereby providing the counter-ion conductance that supports V-ATPase-driven luminal acidification and raises luminal chloride concentration.

ClC-7 acts as the alpha-subunit of an obligate heteromeric complex with the beta-subunit OSTM1, which is required for ClC-7 protein stability and transport activity; the assembled CLCN7-OSTM1 complex is the functional transport unit in lysosomes and the osteoclast ruffled border.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

OpenScientist

OpenScientist

📚 Additional Documentation

Notes

Pn Notes

📄 View Raw YAML