SCNN1G

Summary

SCNN1G (sodium channel epithelial 1 subunit gamma, HGNC:10602) is a protein-coding gene on chromosome 16p12.2, encoding Epithelial sodium channel subunit gamma (P51170). This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis.

Nonvoltage-gated, amiloride-sensitive, sodium channels control fluid and electrolyte transport across epithelia in many organs. These channels are heteromeric complexes consisting of 3 subunits: alpha, beta, and gamma. This gene encodes the gamma subunit, and mutations in this gene have been associated with Liddle syndrome.

Source: NCBI Gene 6340 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Liddle syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 357 total — 9 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes
• MANE Select transcript: NM_001039

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10602
Approved symbol	SCNN1G
Name	sodium channel epithelial 1 subunit gamma
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Aliases	ENaCgamma, SCNEG
Ensembl gene	ENSG00000166828
Ensembl biotype	protein_coding
OMIM	600761
Entrez	6340

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000300061, ENST00000876140, ENST00000876141, ENST00000876142

RefSeq mRNA: 1 — MANE Select: NM_001039 NM_001039

CCDS: CCDS10608

Canonical transcript exons

ENST00000300061 — 13 exons

Exon	Start	End
ENSE00001106996	23189371	23189671
ENSE00001107000	23192352	23192542
ENSE00001107002	23212034	23212151
ENSE00001107004	23186228	23186588
ENSE00001107010	23209750	23209848
ENSE00001107012	23213102	23213163
ENSE00001107013	23212678	23212756
ENSE00001107016	23197264	23197427
ENSE00001107018	23194171	23194274
ENSE00001107020	23214712	23214787
ENSE00001107021	23212837	23212894
ENSE00001213565	23215089	23216883
ENSE00001374870	23182745	23182813

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 96.86.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4988 / max 330.0651, expressed in 270 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153152	1.2914	245
153151	0.1407	57
153153	0.0666	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	96.86	gold quality
kidney epithelium	UBERON:0004819	96.23	gold quality
bronchial epithelial cell	CL:0002328	89.92	gold quality
adult mammalian kidney	UBERON:0000082	89.47	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.13	gold quality
bronchus	UBERON:0002185	87.72	gold quality
lower esophagus mucosa	UBERON:0035834	86.43	gold quality
kidney	UBERON:0002113	85.87	gold quality
adult organism	UBERON:0007023	83.09	gold quality
esophagus squamous epithelium	UBERON:0006920	79.49	gold quality
lower lobe of lung	UBERON:0008949	79.12	gold quality
esophagus mucosa	UBERON:0002469	78.44	gold quality
saliva-secreting gland	UBERON:0001044	77.72	gold quality
minor salivary gland	UBERON:0001830	77.32	gold quality
parotid gland	UBERON:0001831	77.20	gold quality
metanephros cortex	UBERON:0010533	76.51	gold quality
skin of leg	UBERON:0001511	76.21	gold quality
upper lobe of lung	UBERON:0008948	75.61	gold quality
mouth mucosa	UBERON:0003729	75.56	gold quality
upper lobe of left lung	UBERON:0008952	75.55	gold quality
skin of abdomen	UBERON:0001416	75.45	gold quality
lung	UBERON:0002048	74.72	gold quality
zone of skin	UBERON:0000014	74.39	gold quality
vagina	UBERON:0000996	74.31	gold quality
cerebellar cortex	UBERON:0002129	74.23	gold quality
cerebellar hemisphere	UBERON:0002245	74.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	73.94	gold quality
cerebellum	UBERON:0002037	73.66	gold quality
urethra	UBERON:0000057	72.95	gold quality
right hemisphere of cerebellum	UBERON:0014890	72.67	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	816.79
E-GEOD-131882	yes	816.59
E-ANND-3	yes	5.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR3C2, SP1, SP3, SSRP1

miRNA regulators (miRDB)

61 targeting SCNN1G, 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-4283	100.00	66.42	2097
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-486-3P	99.51	66.82	1901

Literature-anchored findings (GeneRIF, showing 40)

• Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel gamma-subunit gene. (PMID:12107247)
• GammaENaC Asn530Ser mutation increases channel open probability and is consistent with abnormally high sodium reabsorption in distal nephron. First mutation in extracellular domain of ENaC subunit with increased ENaC activity and Liddle’s syndrome. (PMID:12473862)
• Not only are CFTR and ENaC activated together in duct salt absorption, but ENaC activation depends on functioning CFTR. (PMID:12548396)
• in ulcerative colitis, elevated proinflammatory cytokines selectively impair beta- and gamma-ENaC expression, which contributes to diarrhea by reducing colonic sodium absorption. (PMID:15188166)
• The roles of these missense mutations in the SCNN1B or SCNN1G gene identified in hypertensive patients are not clear in the pathogenesis of hypertension and the regulation of electrolytes. (PMID:15198480)
• cAMP regulates ENaC in part by phosphorylation and inhibition of Nedd4-2. Moreover, Nedd4-2 is a central convergence point for kinase regulation of Na(+) transport. (PMID:15328345)
• The ENaC expressed in the bladder epithelium might be implicated in the mechanosensory transduction in the bladder afferent pathways, thereby inducing detrusor instability by outlet obstruction. (PMID:15596218)
• Common variants of the ENaC gamma subunit confer susceptibility to human essential hypertension. (PMID:15661075)
• We conclude that overexpression of ClC-5, specifically amino acids 347-647, can alter the normal translation or trafficking of ENaC and other ion transport proteins by a mechanism that is independent of the chloride conductance of ClC-5. (PMID:15702377)
• the interactions of delta-ENaC with alpha beta gamma-human epithelial sodium channel subunits could account for heterogeneity of native epithelial channels (PMID:16423824)
• SCNN1G is a modulator in Cystic Fibrosis. (PMID:16463024)
• These observations decisively prove that Rab27a inhibits ENaC function through a complex mechanism that involves GTP/GDP status, and protein-protein interactions involving Munc13-4 and SLP-5 effector proteins. (PMID:16630545)
• 14-3-3 inhibits the interaction between the WW domains of hNedd4-2 and the PY motif of the epithelial Na(+) channel, ENaC (PMID:16716084)
• A synthetic peptide corresponding to the fragment cleaved from the gamma subunit is a reversible inhibitor of endogenous ENaCs in cells; results suggest that multiple proteases cleave ENaC gamma subunits to fully activate the channel. (PMID:17199078)
• Concerted action of short chain fatty acids and corticosteroid hormones is required for induction of ENaC and maintenance of intestinal electrogenic sodium absorption (PMID:17241874)
• Results support a model whereby ubiquitin and clathrin adaptor binding sites act in concert to remove ENaC from the cell surface. (PMID:17381423)
• This study found that co-expressed cystic fibrosis transmembrane conductance regulator (CFTR) stabilizes epithelial sodium channel(ENaC) at the plasma membrane, suggesting that CFTR regulates ENaC stability, not just opening. (PMID:17434346)
• both mouse and human mammary cells express all ENaC subunits, and they are regulated by steroid hormones in a temporal and cell-specific manner both in culture and in vivo (PMID:17510235)
• genetic variants in ENaCgamma (epithelial sodium channel gamma) genes do not modulate disease severity in the majority of CF patients (PMID:17560176)
• Relatively common polymorphisms in the SCNN1G gene are associated with high systolic blood pressure in the general Australian white population. (PMID:17698725)
• alpha- & beta-hnENaC protein was increased in cystic fibrosis tissue; gamma-hnENaC was decreased; Na+ hyperabsorption not caused by hnENaC mutations, but by an increase in transcription of hnENaC subunits (PMID:17766193)
• protease binding and perhaps cleavage of the gamma subunit results in ENaC activation (PMID:17998393)
• Several variants in ENaCbeta and gamma genes might be deleterious for ENaC function and lead to bronchiectasis. (PMID:18507830)
• Alpha-, beta- and gamma-ENaC messenger RNAs are detected in amiloride-sensitive BeWo trophoblast cells. (PMID:18665318)
• Plasmin activates epithelial Na+ channels by cleaving the gamma subunit (PMID:18981180)
• support a model in which protons modulate ENaC gating by relieving Na(+) self-inhibition (PMID:18990692)
• CF-like syndrome in Africa could be associated with ENaC mutations in Rwandan patients. (PMID:19017867)
• Plasmin in nephrotic urine activates the epithelial sodium channel (PMID:19073825)
• ENaC plays an important role in fluid absorption in the human endolymphatic sac and its function may be altered during inflammatory conditions. (PMID:19300301)
• Regulation of epithelial sodium channels by cGMP/PKGII. (PMID:19359370)
• a significant inhibition of D54-MG cell migration after ASIC1, alphaENaC, or gammaENaC knockdown, consistent with the hypothesis that ENaC/Degenerin subunits play an important role in glioma cell biology. (PMID:19561078)
• These data together suggest that anionic phospholipids differentially regulate epithelial sodium channels (ENaCs) by physically interacting with alpha-, beta-, and gamma-ENaC subunits. (PMID:19763606)
• HOCl and its reactive intermediates (such as organic chloramines) inhibit ENaC by affecting channel gating, which could be relieved by proteases cleavage (PMID:20106988)
• A new nonsense mutation(Q567X) of the SCNN1G gene is likely the cause of Liddle’s syndrome in family 2. (PMID:20376790)
• SPLUNC1 potently reduced surface levels of the epithelial sodium channel (ENaC)in bronchial epithelial cells and Xenopus laevis oocytes. (PMID:20519934)
• Demonstrate that the metalloprotease meprin beta and gamma-ENaC associate directly through cytoplasmic domains. (PMID:20953144)
• Identify the specific domains of epithelial sodium channels that are responsible for the differences in the response to flow of alphabetagamma and deltabetagamma channels. (PMID:21307123)
• variants of ENaC subunits may contribute to the variation of BP response to dietary sodium intake (PMID:21562341)
• Data show that response to apical fluid volume expansion in H441 airway epithelial cells involves cleavage of gammaENaC, and changes in alpha- and gammaENaC protein abundance at the apical membrane. (PMID:21667229)
• The intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly positively associated with higher blood pressure and urinary potassium excretion in 4 white European cohorts. (PMID:22006290)

Cross-species orthologs

26 orthologs

Organism	Symbol	Gene ID
mus_musculus	Scnn1g	ENSMUSG00000000216
rattus_norvegicus	Scnn1g	ENSRNOG00000017842
drosophila_melanogaster	Nach	FBGN0024319
drosophila_melanogaster	ppk28	FBGN0030795
drosophila_melanogaster	ppk17	FBGN0032602
drosophila_melanogaster	ppk6	FBGN0034489
drosophila_melanogaster	ppk12	FBGN0034730
drosophila_melanogaster	ppk29	FBGN0034965
drosophila_melanogaster	ppk24	FBGN0039839
drosophila_melanogaster	ppk22	FBGN0051105
drosophila_melanogaster	ppk8	FBGN0052792
drosophila_melanogaster	ppk5	FBGN0053289
drosophila_melanogaster	ppk16	FBGN0065108
drosophila_melanogaster	ppk11	FBGN0065109
drosophila_melanogaster	ppk9	FBGN0085398
drosophila_melanogaster	ppk18	FBGN0265001
caenorhabditis_elegans		WBGENE00003168
caenorhabditis_elegans		WBGENE00003174
caenorhabditis_elegans		WBGENE00007518
caenorhabditis_elegans		WBGENE00009073
caenorhabditis_elegans		WBGENE00011891
caenorhabditis_elegans	delm-2	WBGENE00016063
caenorhabditis_elegans	acd-1	WBGENE00016064
caenorhabditis_elegans	acd-2	WBGENE00016066
caenorhabditis_elegans		WBGENE00016699
caenorhabditis_elegans		WBGENE00017879

Paralogs (8): ASIC4 (ENSG00000072182), ASIC2 (ENSG00000108684), ASIC1 (ENSG00000110881), SCNN1A (ENSG00000111319), SCNN1D (ENSG00000162572), SCNN1B (ENSG00000168447), ASIC3 (ENSG00000213199), ASIC5 (ENSG00000256394)

Protein

Protein identifiers

Epithelial sodium channel subunit gamma — P51170 (reviewed: P51170)

Alternative names: Amiloride-sensitive sodium channel subunit gamma, Gamma-NaCH, Nonvoltage-gated sodium channel 1 subunit gamma, SCNEG, Sodium channel epithelial 1 subunit gamma

All UniProt accessions (2): P51170, A5X2V1

UniProt curated annotations — full annotation on UniProt →

Function. This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis. ENaC operates in epithelial tissues, where it mediates the electrodiffusion of sodium ions from extracellular fluid through the apical membrane of cells, with water following osmotically. It plays a key role in maintaining sodium homeostasis through electrogenic sodium reabsorption in the kidneys. Additionally, ENaC is essential for airway surface liquid homeostasis, which is crucial for proper mucus clearance.

Subunit / interactions. Component of the heterotrimeric epithelial sodium channel (ENaC) composed of an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit. An additional delta/SCNN1D subunit can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties. Interacts with WWP1 (via WW domains). Interacts with WWP2 (via WW domains); inhibits the channel. Interacts with the full-length immature form of PCSK9 (pro-PCSK9); inhibits ENaC by promoting its proteasomal degradation. Interacts with BPIFA1; the interaction is indirect via SCNN1B and inhibits the proteolytic maturation of SCNN1A and SCNN1G and the activation of ENaC.

Subcellular location. Apical cell membrane.

Tissue specificity. Expressed in kidney (at protein level).

Post-translational modifications. Phosphorylated on serine and threonine residues. Aldosterone and insulin increase the basal level of phosphorylation. Ubiquitinated. Can be ubiquitinated at multiple sites and undergo monoubiquitination and polyubiquitination. Ubiquitination by NEDD4 or NEDD4L inhibits the ENaC channel through endocytosis, intracellular retention and degradation of its individual subunits. ENaC is activated through the proteolytic maturation of its subunits. Furin cleaves the SCNN1G subunit first, followed by cleavage by prostasin (PRSS8), which results in a stepwise increase in the open probability of the channel due to the release of an inhibitory tract. BPIFA1, which is recruited by the SCNN1B subunit, prevents the proteolytic activation of ENaC. N-glycosylated. N-linked glycans are processed to complex type during ENaC complex assembly and transport to the plasma membrane.

Disease relevance. Liddle syndrome 2 (LIDLS2) [MIM:618114] A form of Liddle syndrome, an autosomal dominant disorder characterized by early onset of hypertension, hypokalemic alkalosis, and suppression of plasma renin activity and aldosterone secretion. The disease is caused by variants affecting the gene represented in this entry. Bronchiectasis with or without elevated sweat chloride 3 (BESC3) [MIM:613071] A debilitating respiratory disease characterized by chronic, abnormal dilatation of the bronchi and other cystic fibrosis-like symptoms in the absence of known causes of bronchiectasis (cystic fibrosis, autoimmune diseases, ciliary dyskinesia, common variable immunodeficiency, foreign body obstruction). Clinical features include sub-normal lung function, sinopulmonary infections, chronic productive cough, excessive sputum production, and elevated sweat chloride in some cases. The disease is caused by variants affecting the gene represented in this entry. Pseudohypoaldosteronism 1B3, autosomal recessive (PHA1B3) [MIM:620126] A form of pseudohypoaldosteronism type 1, a rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. The disorder affects multiple organs, and is characterized by an often fulminant presentation in the neonatal period with dehydration, hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive and weight loss. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Originally identified and characterized by its inhibition by the diuretic drug amiloride.

Similarity. Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1G subfamily.

RefSeq proteins (1): NP_001030* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001873	ENaC	Family
IPR004724	ENaC_chordates	Family
IPR020903	ENaC_CS	Conserved_site

Pfam: PF00858

Catalyzed reactions (Rhea), 1 shown:

• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (79 total): strand 21, helix 13, turn 10, disulfide bond 8, sequence variant 8, sequence conflict 6, topological domain 3, glycosylation site 2, transmembrane region 2, site 2, chain 1, mutagenesis site 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6WTH	ELECTRON MICROSCOPY	3.06
9BTG	ELECTRON MICROSCOPY	3.12
9BLR	ELECTRON MICROSCOPY	3.38
9BTU	ELECTRON MICROSCOPY	3.68
6BQN	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51170-F1	80.40	0.48

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): 138–139 (cleavage; by furin); 181–182 (cleavage; by prss8)

Disulfide bonds (8): 100–283, 207–214, 260–267, 372–457, 394–453, 398–449, 407–434, 409–423

Glycosylation sites (2): 209, 497

Mutagenesis-validated functional residues (1):

Position	Phenotype
627	loss of ubiquitination by nedd4l.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-9730628	Sensory perception of salty taste
R-HSA-382551	Transport of small molecules
R-HSA-9709957	Sensory Perception
R-HSA-9717189	Sensory perception of taste
R-HSA-983712	Ion channel transport

MSigDB gene sets: 295 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, AREB6_03, GOCC_CELL_SURFACE, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MONOATOMIC_CATION_TRANSPORT, GCM_PRKCG, GCM_RING1

GO Biological Process (14): intracellular sodium ion homeostasis (GO:0006883), regulation of blood pressure (GO:0008217), sodium ion transmembrane transport (GO:0035725), multicellular organismal-level water homeostasis (GO:0050891), sensory perception of salty taste (GO:0050914), sensory perception of sour taste (GO:0050915), sodium ion homeostasis (GO:0055078), cellular response to acidic pH (GO:0071468), sodium ion import across plasma membrane (GO:0098719), cellular response to aldosterone (GO:1904045), cellular response to vasopressin (GO:1904117), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (5): monoatomic ion channel activity (GO:0005216), ligand-gated sodium channel activity (GO:0015280), WW domain binding (GO:0050699), sodium channel activity (GO:0005272), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), apical plasma membrane (GO:0016324), sodium channel complex (GO:0034706), ciliary transition zone (GO:0035869), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Ion channel transport	1
Sensory perception of taste	1
Sensory Perception	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
sensory perception of taste	2
intracellular monoatomic cation homeostasis	1
sodium ion homeostasis	1
blood circulation	1
regulation of biological quality	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
regulation of body fluid levels	1
multicellular organismal-level chemical homeostasis	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
response to acidic pH	1
cellular response to pH	1
sodium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
cellular response to mineralocorticoid stimulus	1
cellular response to alcohol	1
cellular response to aldehyde	1
cellular response to ketone	1
response to aldosterone	1
cellular response to peptide hormone stimulus	1
response to vasopressin	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
sodium channel activity	1
ligand-gated monoatomic cation channel activity	1
protein domain specific binding	1
monoatomic cation channel activity	1
sodium ion transmembrane transporter activity	1
binding	1
nuclear lumen	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1

Protein interactions and networks

STRING

995 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCNN1G	SCNN1B	P51168	954
SCNN1G	NEDD4L	Q96PU5	915
SCNN1G	NEDD4	P46934	888
SCNN1G	CFTR	P13569	886
SCNN1G	NR3C2	P08235	857
SCNN1G	REN	P00797	850
SCNN1G	SCNN1A	P37088	849
SCNN1G	SLC12A3	P55017	801
SCNN1G	SGK1	O00141	780
SCNN1G	WNK4	Q96J92	728
SCNN1G	SLC12A1	Q13621	717
SCNN1G	KCNJ1	P48048	708
SCNN1G	WNK1	P54963	669
SCNN1G	PRSS8	Q16651	662
SCNN1G	SLC9A3	P48764	646

IntAct

9 interactions, top by confidence:

A	B	Type	Score
SCNN1G	SCNN1A	psi-mi:“MI:0915”(physical association)	0.640
SCNN1A	SCNN1B	psi-mi:“MI:0915”(physical association)	0.490
NEDD4	SCNN1G	psi-mi:“MI:0407”(direct interaction)	0.440
SCNN1G	SCNN1D	psi-mi:“MI:0915”(physical association)	0.400
SCNN1G	MRPL12	psi-mi:“MI:0915”(physical association)	0.400
COMMD1	SCNN1G	psi-mi:“MI:0915”(physical association)	0.400
SCNN1G	SCNN1G	psi-mi:“MI:0915”(physical association)	0.320

BioGRID (33): SCNN1G (Affinity Capture-Western), SCNN1G (Two-hybrid), SCNN1G (Co-fractionation), SCNN1G (Affinity Capture-Western), SCNN1G (Affinity Capture-Western), SCNN1G (Reconstituted Complex), SCNN1G (Reconstituted Complex), SCNN1G (Synthetic Lethality), NEDD4 (Reconstituted Complex), MRPL12 (Proximity Label-MS), SCNN1G (Reconstituted Complex), SCNN1G (Reconstituted Complex), NEDD4 (Far Western), NEDD4L (Far Western), SCNN1G (Positive Genetic)

ESM2 similar proteins: A5D7U4, F1MJW3, H1AFJ5, H1AFJ6, H1AFJ7, H2LRU7, H2QAR5, H2QAR6, H9GBX2, K7FQW8, K7FSQ4, K7GET2, O13262, O13263, O35240, O62816, O70397, O97742, P24585, P24612, P34886, P37090, P37091, P49653, P51167, P51168, P51169, P51170, P51171, P78348, Q17298, Q19038, Q28738, Q60NC0, Q62765, Q62889, Q6NXK8, Q6X1Y6, Q708S3, Q708S7

Diamond homologs: A5D7U4, F1MJW3, H1AFJ5, H1AFJ6, H1AFJ7, H2Q5A1, H2QAR5, H2QAR6, H9GBX2, K7FQW8, K7FSQ4, K7GET2, O13262, O13263, O62816, O97741, O97742, P37088, P37089, P37090, P37091, P51167, P51168, P51169, P51170, P51171, P51172, P55270, Q21974, Q28738, Q61180, Q92075, Q95165, Q9R1N2, Q9W754, Q9WU38, Q9WU39, O46547, Q09274, O01635

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
SCNN1G	“up-regulates activity”	CACNA1H	binding
SCNN1G	“up-regulates quantity”	sodium(1+)	relocalization
MAPK1	“down-regulates quantity by destabilization”	SCNN1G	phosphorylation
MAPK3	“down-regulates quantity by destabilization”	SCNN1G	phosphorylation
Gbeta	“down-regulates quantity by destabilization”	SCNN1G	phosphorylation
ERK1/2	“down-regulates quantity by destabilization”	SCNN1G	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	8
Uncertain significance	193
Likely benign	62
Benign	50

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1323567	NM_001039.4(SCNN1G):c.412C>T (p.Arg138Ter)	Pathogenic
1328113	GRCh37/hg19 16p12.2-11.2(chr16:21594997-29625302)x1	Pathogenic
280615	NM_001039.4(SCNN1G):c.146_149dup (p.Leu51fs)	Pathogenic
561163	NM_001039.4(SCNN1G):c.1699C>T (p.Gln567Ter)	Pathogenic
565277	NM_001039.4(SCNN1G):c.1749_1753del (p.Glu583fs)	Pathogenic
8824	NM_001039.4(SCNN1G):c.1718G>A (p.Trp573Ter)	Pathogenic
8825	NM_001039.4(SCNN1G):c.1570-1G>A	Pathogenic
8826	NM_001039.4(SCNN1G):c.318-1G>A	Pathogenic
8827	NM_001039.4(SCNN1G):c.1627del (p.Val543fs)	Pathogenic
1120080	NM_001039.4(SCNN1G):c.1318C>T (p.Arg440Ter)	Likely pathogenic
2632715	NM_001039.4(SCNN1G):c.1431+1G>T	Likely pathogenic
2752048	NM_001039.4(SCNN1G):c.913+1G>T	Likely pathogenic
3579896	NM_001039.4(SCNN1G):c.416_417del (p.Glu139fs)	Likely pathogenic
4077487	NM_001039.4(SCNN1G):c.92G>A (p.Trp31Ter)	Likely pathogenic
804476	NM_001039.4(SCNN1G):c.142dup (p.Arg48fs)	Likely pathogenic
805493	NM_001039.4(SCNN1G):c.1697G>A (p.Trp566Ter)	Likely pathogenic
817697	NM_001039.4(SCNN1G):c.1278_1288del (p.Gln427fs)	Likely pathogenic

SpliceAI

1671 predictions. Top by Δscore:

Variant	Effect	Δscore
16:23182809:GAAAG:G	donor_gain	1.0000
16:23182811:AAGGT:A	donor_loss	1.0000
16:23182812:AG:A	donor_gain	1.0000
16:23182813:GG:G	donor_gain	1.0000
16:23182813:GGT:G	donor_loss	1.0000
16:23182814:G:GG	donor_gain	1.0000
16:23182814:GTG:G	donor_loss	1.0000
16:23182815:T:A	donor_loss	1.0000
16:23186227:GCAC:G	acceptor_gain	1.0000
16:23186586:CAAG:C	donor_loss	1.0000
16:23186587:AAGT:A	donor_loss	1.0000
16:23186589:G:GG	donor_gain	1.0000
16:23186590:T:G	donor_loss	1.0000
16:23189368:CAG:C	acceptor_loss	1.0000
16:23189369:A:C	acceptor_loss	1.0000
16:23189668:ACTG:A	donor_gain	1.0000
16:23189669:CTG:C	donor_gain	1.0000
16:23189670:TGGT:T	donor_loss	1.0000
16:23189671:GGT:G	donor_loss	1.0000
16:23189672:G:C	donor_loss	1.0000
16:23189672:G:GG	donor_gain	1.0000
16:23189673:T:A	donor_loss	1.0000
16:23192523:G:GT	donor_gain	1.0000
16:23194165:CCATA:C	acceptor_loss	1.0000
16:23194166:CATA:C	acceptor_loss	1.0000
16:23194168:TA:T	acceptor_loss	1.0000
16:23194170:GGA:G	acceptor_gain	1.0000
16:23194273:TGGT:T	donor_loss	1.0000
16:23194274:GGT:G	donor_loss	1.0000
16:23194275:G:T	donor_loss	1.0000

AlphaMissense

4298 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:23194208:T:A	C283S	0.998
16:23194209:G:C	C283S	0.998
16:23212150:G:C	W431C	0.998
16:23212150:G:T	W431C	0.998
16:23186437:T:A	W56R	0.997
16:23186437:T:C	W56R	0.997
16:23186561:T:A	V97D	0.997
16:23186569:T:A	C100S	0.997
16:23186570:G:C	C100S	0.997
16:23194210:C:G	C283W	0.997
16:23212124:T:A	C423S	0.997
16:23212125:G:C	C423S	0.997
16:23215129:T:C	L537P	0.997
16:23215131:T:A	W538R	0.997
16:23215131:T:C	W538R	0.997
16:23215137:A:C	S540R	0.997
16:23215139:C:A	S540R	0.997
16:23215139:C:G	S540R	0.997
16:23186398:C:A	R43S	0.996
16:23186570:G:A	C100Y	0.996
16:23186571:C:G	C100W	0.996
16:23194202:G:T	G281W	0.996
16:23194208:T:C	C283R	0.996
16:23212082:T:A	C409S	0.996
16:23212083:G:C	C409S	0.996
16:23212125:G:A	C423Y	0.996
16:23212126:C:G	C423W	0.996
16:23212728:T:A	C449S	0.996
16:23212729:G:C	C449S	0.996
16:23212740:T:A	C453S	0.996

dbSNP variants (sampled 300 via entrez): RS1000043233 (16:23201809 A>T), RS1000237522 (16:23214135 C>A), RS1000390832 (16:23208053 A>G), RS1000410117 (16:23184608 T>C), RS1000414597 (16:23190381 G>T), RS1000539545 (16:23208279 A>C), RS1000716645 (16:23212573 G>A,T), RS1000917167 (16:23203451 G>A), RS1000996006 (16:23206501 G>A,T), RS1001032855 (16:23187114 T>C), RS1001044281 (16:23200288 T>A), RS1001100140 (16:23200653 T>C), RS1001279554 (16:23206772 C>A,T), RS1001309280 (16:23213507 C>G), RS1001361297 (16:23213711 C>T)

Disease associations

OMIM: gene MIM:600761 | disease phenotypes: MIM:613071, MIM:264350, MIM:618114, MIM:620126, MIM:608779, MIM:252270

GenCC curated gene-disease

Disease	Classification	Inheritance
Liddle syndrome 2	Strong	Autosomal dominant
pseudohypoaldosteronism, type IB1, autosomal recessive	Strong	Autosomal recessive
Liddle syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Liddle syndrome	Definitive	AD

Mondo (8): bronchiectasis with or without elevated sweat chloride 3 (MONDO:0013112), pseudohypoaldosteronism, type IB1, autosomal recessive (MONDO:0009917), Liddle syndrome 2 (MONDO:0020854), pseudohypoaldosteronism, type IB3, autosomal recessive (MONDO:0859318), myoepithelial tumor (MONDO:0002380), COG7-congenital disorder of glycosylation (MONDO:0012118), monosomy 7 myelodysplasia and leukemia syndrome 1 (MONDO:0009646), Liddle syndrome (MONDO:0008323)

Orphanet (4): Idiopathic bronchiectasis (Orphanet:60033), Generalized pseudohypoaldosteronism type 1 (Orphanet:171876), Pseudohypoaldosteronism type 1 (Orphanet:756), COG7-CDG (Orphanet:79333)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000112	Nephropathy
HP:0000822	Hypertension
HP:0000848	Increased circulating renin concentration
HP:0000859	Increased circulating aldosterone concentration
HP:0001047	Atopic dermatitis
HP:0001081	Cholelithiasis
HP:0001217	Clubbing
HP:0001324	Muscle weakness
HP:0001531	Failure to thrive in infancy
HP:0001658	Myocardial infarction
HP:0001824	Weight loss
HP:0001942	Metabolic acidosis
HP:0001944	Dehydration
HP:0001945	Fever
HP:0002013	Vomiting
HP:0002019	Constipation
HP:0002094	Dyspnea
HP:0002097	Emphysema
HP:0002105	Hemoptysis
HP:0002110	Bronchiectasis
HP:0002153	Hyperkalemia
HP:0002637	Cerebral ischemia
HP:0002754	Osteomyelitis
HP:0002783	Recurrent lower respiratory tract infections
HP:0002795	Abnormal respiratory system physiology
HP:0002900	Hypokalemia
HP:0002902	Hyponatremia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006979_652	Heel bone mineral density	1.000000e-19
GCST010605_12	Parent of origin effect on receptive language ability (paternal)	1.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0005686	receptive language perception
EFO:0005939	parental genotype effect measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D056929	Liddle Syndrome	C12.050.351.968.419.815.683; C12.200.777.419.815.683; C12.950.419.815.683; C16.320.831.698
D009208	Myoepithelioma	C04.557.435.585
C567772	Bronchiectasis With Or Without Elevated Sweat Chloride 3 (supp.)
C535754	Congenital disorder of glycosylation type 2E (supp.)
C565370	Monosomy 7 of Bone Marrow (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1628484 (SINGLE PROTEIN), CHEMBL2107836 (PROTEIN COMPLEX)

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5723	SCNN1G		0.00	0
rs5729	SCNN1G		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Epithelial sodium channel (ENaC)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.77	IC50	17	nM	CHEMBL5303508

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases reaction, increases methylation, increases reaction, decreases expression	3
Amiloride	affects binding, decreases reaction, increases transport, decreases activity	3
Sodium	decreases reaction, increases transport, affects transport, affects binding	3
sodium arsenite	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Dexamethasone	decreases expression, decreases reaction, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Valproic Acid	increases expression, increases methylation	2
bisphenol F	decreases expression	1
lead acetate	decreases expression	1
methylparaben	decreases expression	1
tetrabromobisphenol A	decreases expression	1
tobacco tar	decreases expression	1
cupric chloride	decreases expression	1
8-((4-chlorophenyl)thio)cyclic-3’,5’-GMP	affects binding, increases activity	1
acetylleucyl-leucyl-norleucinal	decreases expression, increases methylation	1
8-(4-chlorophenylthio)guanosine 3’,5’-cyclic monophosphorothioate	increases activity, affects binding	1
CGP 52608	affects binding, increases reaction	1
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases expression, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
bisphenol S	decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	decreases reaction, decreases expression	1
Aldosterone	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1

ChEMBL screening assays

5 unique, capped per target: 3 binding, 1 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4200636	ADMET	Inhibition of S-3969-stimulated recombinant human ENaC gamma subunit expressed in HEK293 cells at 10 uM preincubated for 5 mins followed by S-3969 stimulation by FLIPR assay	6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer. — J Med Chem
CHEMBL2051232	Binding	Inhibition of human ENaC alpha-beta-gamma expressed in Xenopus laevis oocytes assessed as effect on transmembrane currents at 1 mM by two-electrode voltage-clamp technique	Thiol-reactive compounds from garlic inhibit the epithelial sodium channel (ENaC). — Bioorg Med Chem
CHEMBL5304011	Functional	Inhibition of Na+ current by Ussing Chamber	Data for DCP probe BI-8668

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis