LRRC8A

Summary

LRRC8A (leucine rich repeat containing 8 VRAC subunit A, HGNC:19027) is a protein-coding gene on chromosome 9q34.11, encoding Volume-regulated anion channel subunit LRRC8A (Q8IWT6). Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes.

This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. This family member is a putative four-pass transmembrane protein that plays a role in B cell development. Defects in this gene cause autosomal dominant non-Bruton type agammaglobulinemia, an immunodeficiency disease resulting from defects in B cell maturation. Multiple alternatively spliced transcript variants, which encode the same protein, have been identified for this gene.

Source: NCBI Gene 56262 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal agammaglobulinemia (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 535 total
• Phenotypes (HPO): 31
• MANE Select transcript: NM_019594

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19027
Approved symbol	LRRC8A
Name	leucine rich repeat containing 8 VRAC subunit A
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1437, FLJ10337, SWELL1
Ensembl gene	ENSG00000136802
Ensembl biotype	protein_coding
OMIM	608360
Entrez	56262

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 38 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000259324, ENST00000372599, ENST00000372600, ENST00000483638, ENST00000492784, ENST00000867202, ENST00000867203, ENST00000867204, ENST00000867205, ENST00000867206, ENST00000867207, ENST00000867208, ENST00000867209, ENST00000867210, ENST00000867211, ENST00000867212, ENST00000867213, ENST00000867214, ENST00000927466, ENST00000927467, ENST00000927468, ENST00000927469, ENST00000927470, ENST00000927471, ENST00000927472, ENST00000927473, ENST00000927474, ENST00000927475, ENST00000927476, ENST00000927477, ENST00000964726, ENST00000964727, ENST00000964728, ENST00000964729, ENST00000964730, ENST00000964731, ENST00000964732, ENST00000964733, ENST00000964734, ENST00000964735

RefSeq mRNA: 3 — MANE Select: NM_019594 NM_001127244, NM_001127245, NM_019594

CCDS: CCDS35155

Canonical transcript exons

ENST00000372600 — 4 exons

Exon	Start	End
ENSE00001178872	128907157	128909321
ENSE00001458184	128886015	128886121
ENSE00001458185	128882133	128882250
ENSE00001814641	128916096	128918039

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 99.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.1636 / max 190.9664, expressed in 1809 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98844	23.9800	1809
98850	0.5613	365
98854	0.3642	157
98845	0.1676	81
98853	0.0346	11
98852	0.0299	7
98855	0.0259	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	99.10	gold quality
nasal cavity epithelium	UBERON:0005384	98.46	gold quality
gingiva	UBERON:0001828	98.42	gold quality
decidua	UBERON:0002450	98.33	gold quality
visceral pleura	UBERON:0002401	98.17	gold quality
lateral globus pallidus	UBERON:0002476	98.03	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.80	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.69	gold quality
adult organism	UBERON:0007023	97.63	gold quality
entorhinal cortex	UBERON:0002728	97.62	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.62	gold quality
esophagus squamous epithelium	UBERON:0006920	97.58	gold quality
upper arm skin	UBERON:0004263	97.49	gold quality
substantia nigra pars compacta	UBERON:0001965	97.48	gold quality
parietal pleura	UBERON:0002400	97.45	gold quality
parotid gland	UBERON:0001831	97.40	gold quality
lower lobe of lung	UBERON:0008949	97.30	gold quality
middle temporal gyrus	UBERON:0002771	97.23	gold quality
postcentral gyrus	UBERON:0002581	97.13	gold quality
left ventricle myocardium	UBERON:0006566	97.06	gold quality
seminal vesicle	UBERON:0000998	97.02	gold quality
trigeminal ganglion	UBERON:0001675	97.01	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.89	gold quality
parietal lobe	UBERON:0001872	96.84	gold quality
pancreatic ductal cell	CL:0002079	96.73	gold quality
ventral tegmental area	UBERON:0002691	96.68	gold quality
amniotic fluid	UBERON:0000173	96.64	gold quality
pharyngeal mucosa	UBERON:0000355	96.58	gold quality
cartilage tissue	UBERON:0002418	96.54	gold quality
oral cavity	UBERON:0000167	96.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	59.71
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

77 targeting LRRC8A, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-8080	99.82	67.52	1342

Literature-anchored findings (GeneRIF, showing 37)

• Includes the cloning of this gene, designated as KIAA1437. (PMID:10718198)
• LRRC8 is required for B cell development. (PMID:14660746)
• identified four genes, named TA-LRRP, AD158, LRRC5, and FLJ23420, as unknown LRRC8-like genes (PMID:15094057)
• Study identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous volume-regulated anion channel currents and regulatory cell volume decrease in various cell types. (PMID:24725410)
• Genomic disruption of LRRC8A ablated volume-regulated anion channel (VRAC) currents. Cells with disruption of all five LRRC8 genes required LRRC8A cotransfection with other LRRC8 isoforms to reconstitute VRAC currents. (PMID:24790029)
• LRRC8A is an essential regulator of cisplatin induced p53 protein activity and its downstream signaling involving increased expression of p21Waf1/Cip1 and MDM2, as well as activation of caspase-9 and -3 in tumor cell lines. (PMID:26984736)
• It has been demonstrated in ovarian cancer cells that cisplatin resistance and uptake correlates with reduced CTR1 and LRRC8A protein expression/activity and a concomitant upregulation in cisplatin exporting transporters (ATP7A, ATP7B), which implies that the resistant cells have a reduced ability to accumulate cisplatin and activate proapoptotic transporters for osmolytes. (PMID:27112899)
• Inactivation and Anion Selectivity of Volume-regulated Anion Channels (VRACs) Depend on C-terminal Residues of the First Extracellular Loop. (PMID:27325695)
• These data suggest that LRRC8A is associated with the deceleration mechanism of Volume-sensitive outwardly rectifying anion channel inactivation, while none of LRRC8 members is related to the acceleration mechanism. (PMID:27579940)
• volume-sensitive outwardly rectifying currents were found to be largely reduced by siRNA against LRRC8A (PMID:27764579)
• LRRC8A channels support TNFalpha-induced superoxide production by Nox1 which is required for receptor endocytosis. (PMID:27838438)
• LRRC8 channels transport the neurotransmitters glutamate, aspartate and gamma-aminobutyric acid (GABA) and the co-activator D-serine. (PMID:28193731)
• Identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance. (PMID:28436964)
• using cryo-electron microscopy and X-ray crystallography, determination of the structure of a homomeric channel of the obligatory subunit LRRC8A; this work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction (PMID:29769723)
• The study shows here that the short stretch preceding the first LRRC8 transmembrane domain determines volume-regulated anion channels conductance, ion permeability, and inactivation gating. Substituted-cysteine accessibility studies revealed that several of the first 15 LRRC8 residues are functionally important and exposed to a hydrophilic environment. (PMID:29925591)
• High LRRC8A expression is associated with colon cancer cell growth and metastasis. (PMID:30015914)
• a mutation in the flexible N-terminal portion of SWELL1 affects pore properties, suggesting a putative link between intracellular structures and channel regulation. This structure provides a scaffold for further dissecting the heterogeneity and mechanism of activation of VRAC. (PMID:30095067)
• Comparing the two conformations suggests that the LRR region is flexible and mobile, with rigid-body motions, which might be implicated in structural transitions on pore opening (PMID:30127360)
• LRRC8A has a role in hypotonic stress response of human keratinocytes (PMID:30252954)
• The LRRC8-mediated volume-regulated anion channel is altered in glaucoma. (PMID:30931966)
• Non-vesicular release of glutamate through the glutamate-permeable volume-regulated anion channel (VRAC). Both cell swelling and receptor stimulation activated astrocytic VRAC, which requires its only obligatory subunit, Swell1. (PMID:30982627)
• It discusses the recent molecular biological insights into the physiology of LRRC8A as the pore-forming components of volume-regulated anion channel (VRAC) in relation to its previously proposed roles. (PMID:31091194)
• Knockdown of LRRC8A ameliorates AngII-induced cerebrovascular smooth muscle cell proliferation via inhibiting PI3K/AKT pathway, suggesting that LRRC8A may be a novel molecular target in the treatment of vascular remodeling and stroke. (PMID:31127489)
• High LRRC8A expression is associated with Esophageal Squamous Cell Carcinoma. (PMID:31323188)
• LRRC8/VRAC channels exhibit a noncanonical permeability to glutathione, which modulates epithelial-to-mesenchymal transition (EMT). (PMID:31804464)
• LRRC8 family proteins within lysosomes regulate cellular osmoregulation and enhance cell survival to multiple physiological stresses. (PMID:33139539)
• LRRC8A homohexameric channels poorly recapitulate VRAC regulation and pharmacology. (PMID:33356947)
• Volume-regulated chloride channel regulates cell proliferation and is involved in the possible interaction between TMEM16A and LRRC8A in human metastatic oral squamous cell carcinoma cells. (PMID:33476655)
• LRRC8A influences the growth of gastric cancer cells via the p53 signaling pathway. (PMID:33864161)
• Oxidant-resistant LRRC8A/C anion channels support superoxide production by NADPH oxidase 1. (PMID:33932953)
• LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions. (PMID:34083438)
• Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes. (PMID:35145074)
• LRRC8A is responsible for exosome biogenesis and volume regulation in colon cancer cells. (PMID:37129855)
• Physiological Functions of the Volume-Regulated Anion Channel VRAC/LRRC8 and the Proton-Activated Chloride Channel ASOR/TMEM206. (PMID:37468723)
• Swell1 channel-mediated tonic GABA release from astrocytes modulates cocaine reward. (PMID:37524750)
• Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels. (PMID:37543949)
• LRRC8A as a central mediator promotes colon cancer metastasis by regulating PIP5K1B/PIP2 pathway. (PMID:38350542)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrrc8aa	ENSDARG00000032188
danio_rerio	lrrc8ab	ENSDARG00000052155
mus_musculus	Lrrc8a	ENSMUSG00000007476
rattus_norvegicus	Lrrc8a	ENSRNOG00000025296

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), PHLPP1 (ENSG00000081913), SHOC2 (ENSG00000108061), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRK1 (ENSG00000154237), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8C (ENSG00000171488), LRRC8D (ENSG00000171492), PIDD1 (ENSG00000177595), SCRIB (ENSG00000180900), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954), LRRD1 (ENSG00000240720)

Protein

Protein identifiers

Volume-regulated anion channel subunit LRRC8A — Q8IWT6 (reviewed: Q8IWT6)

Alternative names: Leucine-rich repeat-containing protein 8A, Swelling protein 1

All UniProt accessions (1): Q8IWT6

UniProt curated annotations — full annotation on UniProt →

Function. Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine. Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress. LRRC8A and LRRC8D are required for the uptake of the drug cisplatin. In complex with LRRC8C or LRRC8E, acts as a transporter of immunoreactive cyclic dinucleotide GMP-AMP (2’-3’-cGAMP), an immune messenger produced in response to DNA virus in the cytosol: mediates both import and export of 2’-3’-cGAMP, thereby promoting transfer of 2’-3’-cGAMP to bystander cells. In contrast, complexes containing LRRC8D inhibit transport of 2’-3’-cGAMP. Required for in vivo channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. Can form functional channels by itself (in vitro). Involved in B-cell development: required for the pro-B cell to pre-B cell transition. Also required for T-cell development. Required for myoblast differentiation: VRAC activity promotes membrane hyperpolarization and regulates insulin-stimulated glucose metabolism and oxygen consumption. Also acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion. Also plays a role in lysosome homeostasis by forming functional lysosomal VRAC channels in response to low cytoplasmic ionic strength condition: lysosomal VRAC channels are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis. Acts as a key factor in NLRP3 inflammasome activation by modulating itaconate efflux and mitochondria function.

Subunit / interactions. Heterohexamer; oligomerizes with other LRRC8 proteins (LRRC8B, LRRC8C, LRRC8D and/or LRRC8E) to form a heterohexamer. Can form homohexamers in vitro, but these have lower conductance than heterohexamers. In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist. Interact with GRB2. Interacts with NOX4; this interaction prevents the ubiquitin-mediated degradation of LRRC8A.

Subcellular location. Cell membrane. Lysosome membrane.

Tissue specificity. Expressed in brain, kidney, ovary, lung, liver, heart, and fetal brain and liver. Found at high levels in bone marrow; lower levels are detected in peripheral blood cells. Expressed on T-cells as well as on B-lineage cells.

Post-translational modifications. N-glycosylated.

Disease relevance. Agammaglobulinemia 5, autosomal dominant (AGM5) [MIM:613506] A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving LRRC8 has been found in a patient with congenital agammaglobulinemia. Translocation t(9;20)(q33.2;q12). The translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains.

Activity regulation. Inhibited by (4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid), which plugs the channel like a cork in a bottle by binding in the extracellular selectivity filter and sterically occluding ion conduction. Lipids may block conduction in closed heterohexameric channels.

Domain organisation. The volume-regulated anion channel (VRAC) channel forms a trimer of dimers, with symmetry mismatch between the pore-forming domain and the cytosolic LRR repeats, a topology similar to gap junction proteins. The di-leucine motif is required for lysosomal localization. The cytoplasmic N-terminus preceding the first transmembrane (residues 1-22) regulates volume-regulated anion channel (VRAC) conductance, ion permeability and inactivation gating.

Similarity. Belongs to the LRRC8 family.

RefSeq proteins (3): NP_001120716, NP_001120717, NP_062540* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR021040	LRRC8_Pannexin-like	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family
IPR055414	LRR_R13L4/SHOC2-like	Domain

Pfam: PF12534, PF13855, PF23598

Catalyzed reactions (Rhea), 7 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• myo-inositol(out) = myo-inositol(in) (RHEA:32867)
• 2’,3’-cGAMP(out) = 2’,3’-cGAMP(in) (RHEA:66320)
• iodide(out) = iodide(in) (RHEA:66324)
• taurine(out) = taurine(in) (RHEA:66328)
• L-aspartate(out) = L-aspartate(in) (RHEA:66332)
• L-glutamate(out) = L-glutamate(in) (RHEA:66336)

UniProt features (112 total): helix 35, strand 20, repeat 17, mutagenesis site 9, turn 6, topological domain 5, modified residue 5, transmembrane region 4, disulfide bond 3, glycosylation site 2, sequence conflict 2, chain 1, short sequence motif 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
7XZH	ELECTRON MICROSCOPY	2.78
9O5K	ELECTRON MICROSCOPY	3.19
8DXN	ELECTRON MICROSCOPY	3.4
8DXO	ELECTRON MICROSCOPY	3.6
8DXP	ELECTRON MICROSCOPY	3.7
8DXQ	ELECTRON MICROSCOPY	3.8
8DXR	ELECTRON MICROSCOPY	4
5ZSU	ELECTRON MICROSCOPY	4.25
6DJB	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IWT6-F1	85.52	0.62

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 (1): 103 (required for anion selectivity)

Post-translational modifications (5): 1, 200, 202, 215, 217

Disulfide bonds (3): 54–310, 57–65, 113–295

Glycosylation sites (2): 66, 83

Mutagenesis-validated functional residues (9):

Position	Phenotype
5	no effect.
5	anion channel is more selective to iodite compared to chloride.
6	decreased amplitudes of swelling-activated currents.
44	altered anion selectivity.
66	abolishes n-glycosylation; when associated with a-83.
83	abolishes n-glycosylation; when associated with a-66.
103	affects ion selectivity of the channel.
103	abolished ability to transport 2’-3’-cgamp.
706–707	abolished localization to lysosomes.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5223345	Miscellaneous transport and binding events
R-HSA-382551	Transport of small molecules

MSigDB gene sets: 357 (showing top): RNGTGGGC_UNKNOWN, GCM_MAP4K4, GOBP_B_CELL_ACTIVATION, GOCC_VACUOLAR_MEMBRANE, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, GOBP_HORMONE_TRANSPORT, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_MALE_GAMETE_GENERATION, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_NUCLEOTIDE_TRANSPORT, EFC_Q6

GO Biological Process (18): intracellular glucose homeostasis (GO:0001678), pre-B cell differentiation (GO:0002329), monoatomic anion transport (GO:0006820), cell volume homeostasis (GO:0006884), response to osmotic stress (GO:0006970), spermatogenesis (GO:0007283), taurine transmembrane transport (GO:0015734), aspartate transmembrane transport (GO:0015810), positive regulation of insulin secretion (GO:0032024), protein hexamerization (GO:0034214), positive regulation of myoblast differentiation (GO:0045663), monoatomic anion transmembrane transport (GO:0098656), cyclic-GMP-AMP transmembrane import across plasma membrane (GO:0140361), chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), obsolete organic anion transport (GO:0015711), cell differentiation (GO:0030154), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (5): volume-sensitive anion channel activity (GO:0005225), identical protein binding (GO:0042802), cyclic-GMP-AMP transmembrane transporter activity (GO:0140360), monoatomic anion channel activity (GO:0005253), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
monoatomic ion transport	2
nitrogen compound transport	2
glucose homeostasis	1
intracellular chemical homeostasis	1
immature B cell differentiation	1
regulation of cell size	1
cellular homeostasis	1
response to stress	1
response to abiotic stimulus	1
developmental process involved in reproduction	1
male gamete generation	1
alkanesulfonate transmembrane transport	1
amino acid transmembrane transport	1
C4-dicarboxylate transport	1
acidic amino acid transport	1
carboxylic acid transmembrane transport	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
protein complex oligomerization	1
myoblast differentiation	1
positive regulation of cell differentiation	1
regulation of myoblast differentiation	1
monoatomic anion transport	1
monoatomic ion transmembrane transport	1
purine ribonucleotide transport	1
adenine nucleotide transport	1
cyclic nucleotide transport	1
import across plasma membrane	1
guanine nucleotide transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
transport	1
cellular developmental process	1
transmembrane transport	1
monoatomic anion channel activity	1
protein binding	1
adenine nucleotide transmembrane transporter activity	1

Protein interactions and networks

STRING

1320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRC8A	BEST1	O76090	741
LRRC8A	IGLL1	P15814	733
LRRC8A	ANO1	Q5XXA6	718
LRRC8A	HEPACAM	Q14CZ8	695
LRRC8A	PGM3	O95394	692
LRRC8A	KCNJ10	P78508	670
LRRC8A	CD79B	P40259	658
LRRC8A	BLNK	Q8WV28	655
LRRC8A	TRPV4	Q9HBA0	641
LRRC8A	CLCN3	P51790	621
LRRC8A	KCP	Q6ZWJ8	614
LRRC8A	CD79A	P11912	582
LRRC8A	LRRC8B	Q6P9F7	580
LRRC8A	GJA1	P17302	559
LRRC8A	TTYH2	Q9BSA4	548

IntAct

103 interactions, top by confidence:

A	B	Type	Score
LRRC8A	LRRC8B	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LRRC8A	LRRC8A	psi-mi:“MI:0915”(physical association)	0.650
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
TMEM30B	KLRG2	psi-mi:“MI:0914”(association)	0.530
GYPB	TCAF2	psi-mi:“MI:0914”(association)	0.530
LRRC8B	SLC25A17	psi-mi:“MI:0914”(association)	0.530
STS	GJA1	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
LRRC8A	LRRC8E	psi-mi:“MI:0915”(physical association)	0.520
LRRC8A	LRRC8D	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (131): LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), LRRC8A (Affinity Capture-MS)

ESM2 similar proteins: A0JM56, A2VE70, A5PK13, A6H639, A8WG88, F1QWA8, H2MCM1, O35638, P50851, Q08AM6, Q1RLX4, Q28EW0, Q3KRC6, Q3UUQ7, Q498T9, Q4V8I7, Q5DU41, Q5RAG3, Q5U308, Q5ZIW5, Q66JT1, Q66L58, Q68F38, Q68F79, Q6NSJ5, Q6NU09, Q6P9F7, Q6WRX3, Q75T13, Q765A7, Q7L1W4, Q7Z7L7, Q80TR8, Q80W92, Q80WG5, Q80WQ2, Q80ZJ6, Q8BGR2, Q8BR76, Q8BXN9

Diamond homologs: A5PK13, Q3KRC6, Q498T9, Q4V8I7, Q5DU41, Q5U308, Q66JT1, Q68F79, Q6NSJ5, Q6NU09, Q6P9F7, Q7L1W4, Q80WG5, Q8BGR2, Q8IWT6, Q8R502, Q8TDW0, A6H6A4, A6NIV6, Q9Z1S7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transmembrane transport	6	11.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	286
Likely benign	210
Benign	23

Top pathogenic / likely-pathogenic (0)

SpliceAI

743 predictions. Top by Δscore:

Variant	Effect	Δscore
9:128882248:CAGG:C	donor_loss	1.0000
9:128882249:AGG:A	donor_loss	1.0000
9:128882251:GT:G	donor_loss	1.0000
9:128886119:GGG:G	donor_gain	1.0000
9:128886120:GGG:G	donor_gain	1.0000
9:128899267:GA:G	donor_gain	1.0000
9:128907154:TAGGT:T	acceptor_loss	1.0000
9:128907155:A:AG	acceptor_gain	1.0000
9:128907155:AGGTT:A	acceptor_gain	1.0000
9:128907156:G:GC	acceptor_loss	1.0000
9:128907156:G:GG	acceptor_gain	1.0000
9:128907156:GGTT:G	acceptor_gain	1.0000
9:128907156:GGTTG:G	acceptor_gain	1.0000
9:128916091:TCCA:T	acceptor_loss	1.0000
9:128916092:CCAG:C	acceptor_loss	1.0000
9:128916094:A:AG	acceptor_gain	1.0000
9:128916094:A:C	acceptor_loss	1.0000
9:128916094:AGATC:A	acceptor_gain	1.0000
9:128916095:G:GC	acceptor_gain	1.0000
9:128916095:GA:G	acceptor_gain	1.0000
9:128916095:GAT:G	acceptor_gain	1.0000
9:128916095:GATC:G	acceptor_gain	1.0000
9:128916095:GATCG:G	acceptor_gain	1.0000
9:128882251:G:GG	donor_gain	0.9900
9:128886014:GGGA:G	acceptor_gain	0.9900
9:128886118:TGGGG:T	donor_loss	0.9900
9:128886120:GG:G	donor_gain	0.9900
9:128886121:GG:G	donor_gain	0.9900
9:128886122:G:GG	donor_gain	0.9900
9:128886122:GT:G	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000023948 (9:128889378 G>A), RS1000081263 (9:128912647 G>A), RS1000181240 (9:128913882 A>G), RS1000242541 (9:128917351 A>G,T), RS1000249576 (9:128895949 C>G), RS1000421078 (9:128885488 C>T), RS1000537866 (9:128912387 C>A,T), RS1000726271 (9:128889481 T>G), RS1000754412 (9:128883742 A>C), RS1000782215 (9:128913317 C>A), RS1000790852 (9:128890564 G>A,C), RS1000819068 (9:128895330 C>T), RS1001030823 (9:128890727 A>C), RS1001033877 (9:128901088 G>T), RS1001195662 (9:128897271 C>A,T)

Disease associations

OMIM: gene MIM:608360 | disease phenotypes: MIM:613506

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal agammaglobulinemia	Supportive	Autosomal dominant
agammaglobulinemia 5, autosomal dominant	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
agammaglobulinemia	Limited	AD

Mondo (2): agammaglobulinemia 5, autosomal dominant (MONDO:0013290), autosomal agammaglobulinemia (MONDO:0011096)

Orphanet (0):

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000218	High palate
HP:0000246	Sinusitis
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000389	Chronic otitis media
HP:0000509	Conjunctivitis
HP:0000988	Skin rash
HP:0001287	Meningitis
HP:0001369	Arthritis
HP:0001508	Failure to thrive
HP:0001581	Recurrent skin infections
HP:0001875	Decreased total neutrophil count
HP:0001944	Dehydration
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0002754	Osteomyelitis
HP:0004432	Agammaglobulinemia
HP:0012115	Hepatitis
HP:0012378	Fatigue
HP:0012735	Cough
HP:0100658	Cellulitis
HP:0100806	Sepsis

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005038_22	Allergic disease (asthma, hay fever or eczema)	3.000000e-09
GCST012353_3	Serum metabolite concentrations in chronic kidney disease	2.000000e-12
GCST012353_36	Serum metabolite concentrations in chronic kidney disease	2.000000e-42
GCST90002395_60	Mean platelet volume	5.000000e-09

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538056	Agammaglobulinemia, non-Bruton type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
entinostat	decreases expression	1
K 7174	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
licochalcone B	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Rosiglitazone	decreases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Azathioprine	increases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Carbamazepine	affects expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dimethyl Sulfoxide	decreases expression	1
Ivermectin	decreases expression	1
Rotenone	decreases expression	1
Silver	increases expression	1
Dihydrotestosterone	increases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D9IV	Ubigene HEK293 LRRC8A KO	Transformed cell line	Female
CVCL_SV94	HAP1 LRRC8A (-) 1	Cancer cell line	Male
CVCL_SV95	HAP1 LRRC8A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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