SCNN1A

Summary

SCNN1A (sodium channel epithelial 1 subunit alpha, HGNC:10599) is a protein-coding gene on chromosome 12p13.31, encoding Epithelial sodium channel subunit alpha (P37088). 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 alpha subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), a rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 6337 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pseudohypoaldosteronism, type IB1, autosomal recessive (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 443 total — 22 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 80
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001038

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10599
Approved symbol	SCNN1A
Name	sodium channel epithelial 1 subunit alpha
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	ENaCalpha
Ensembl gene	ENSG00000111319
Ensembl biotype	protein_coding
OMIM	600228
Entrez	6337

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 19 protein_coding, 16 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000228916, ENST00000338748, ENST00000360168, ENST00000366131, ENST00000396966, ENST00000457871, ENST00000536087, ENST00000536176, ENST00000536411, ENST00000536788, ENST00000538957, ENST00000538979, ENST00000539030, ENST00000539953, ENST00000540037, ENST00000541249, ENST00000542260, ENST00000542436, ENST00000542966, ENST00000543585, ENST00000543768, ENST00000544882, ENST00000545605, ENST00000868221, ENST00000868222, ENST00000868223, ENST00000868224, ENST00000868225, ENST00000868226, ENST00000868227, ENST00000868228, ENST00000868229, ENST00000868230, ENST00000868231, ENST00000868232, ENST00000930631

RefSeq mRNA: 3 — MANE Select: NM_001038 NM_001038, NM_001159575, NM_001159576

CCDS: CCDS53738, CCDS53739, CCDS8543

Canonical transcript exons

ENST00000228916 — 13 exons

Exon	Start	End
ENSE00000936986	6363443	6363710
ENSE00000936987	6362051	6362241
ENSE00002263715	6346847	6348253
ENSE00002293408	6375505	6375563
ENSE00003473256	6348950	6349005
ENSE00003483519	6354750	6354848
ENSE00003515810	6374368	6374837
ENSE00003525854	6349327	6349405
ENSE00003570590	6349164	6349221
ENSE00003589571	6348727	6348802
ENSE00003628543	6354438	6354555
ENSE00003643034	6355777	6355880
ENSE00003686451	6355272	6355435

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.46.

FANTOM5 (CAGE): breadth broad, TPM avg 9.4049 / max 434.4104, expressed in 555 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129083	4.4247	409
129085	2.0667	288
129081	0.8130	178
129090	0.4840	181
129084	0.3277	129
129089	0.2370	119
129076	0.1774	82
129082	0.1398	63
129078	0.1336	53
129077	0.1030	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	99.46	gold quality
metanephros cortex	UBERON:0010533	99.14	gold quality
right uterine tube	UBERON:0001302	99.13	gold quality
pancreatic ductal cell	CL:0002079	99.02	gold quality
tongue squamous epithelium	UBERON:0006919	98.79	gold quality
lower esophagus mucosa	UBERON:0035834	98.78	gold quality
renal medulla	UBERON:0000362	98.75	gold quality
esophagus squamous epithelium	UBERON:0006920	98.72	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.70	gold quality
epithelium of esophagus	UBERON:0001976	98.49	gold quality
squamous epithelium	UBERON:0006914	98.45	gold quality
gingival epithelium	UBERON:0001949	98.39	gold quality
mucosa of transverse colon	UBERON:0004991	98.31	gold quality
minor salivary gland	UBERON:0001830	98.29	gold quality
left lobe of thyroid gland	UBERON:0001120	98.24	gold quality
mouth mucosa	UBERON:0003729	98.23	gold quality
nasal cavity mucosa	UBERON:0001826	98.12	gold quality
esophagus mucosa	UBERON:0002469	98.05	gold quality
gingiva	UBERON:0001828	98.01	gold quality
saliva-secreting gland	UBERON:0001044	97.96	gold quality
pharyngeal mucosa	UBERON:0000355	97.93	gold quality
palpebral conjunctiva	UBERON:0001812	97.93	gold quality
epithelium of bronchus	UBERON:0002031	97.93	gold quality
bronchus	UBERON:0002185	97.91	gold quality
right lobe of thyroid gland	UBERON:0001119	97.89	gold quality
bronchial epithelial cell	CL:0002328	97.74	gold quality
ileal mucosa	UBERON:0000331	97.70	gold quality
amniotic fluid	UBERON:0000173	97.67	gold quality
thyroid gland	UBERON:0002046	97.56	gold quality
cervix squamous epithelium	UBERON:0006922	97.53	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	211.63
E-ANND-3	yes	22.70
E-GEOD-109979	no	96.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CLOCK, DNMT1, DNMT3B, FOXC1, GLI3, HMGA2, IL1B, KLF12, KMT2A, LHX8, MLLT3, NCOA1, NFYC, NR1I2, NR3C1, NR3C2, PPARG, RNF2, SMAD4, SP1, SP3, STAT5A, TBX15, TNF, ZHX2

miRNA regulators (miRDB)

47 targeting SCNN1A, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-5001-3P	98.91	67.28	1394

Literature-anchored findings (GeneRIF, showing 40)

• protease-mediated regulation of sodium absorption is a function of human airway epithelia, and prostasin is a likely candidate for this activity. (PMID:11756432)
• Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-subunit gene. (PMID:12107247)
• PPARgamma activation enhances cell surface ENaCalpha via up-regulation of SGK1 in collecting duct cells. (PMID:12923071)
• halphaT663A is a functional polymorphism that affects human ENaC surface expression (PMID:15069064)
• In the mature prenatal lung, subsets of alveolar type II (ATII) cells expressed one or both of the alpha-ENaC transcripts (PMID:15169674)
• Alpha ENaC-deficient transgenic mice represent the first model of constitutively impaired respiratory transepithelial sodium transport and provide direct evidence that this impairment facilitates pulmonary edema in conscious freely moving animals. (PMID:15308680)
• 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)
• dexamethasone caused concentration-dependent activation of the human alpha-ENaC promoter (PMID:15498559)
• 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)
• We determined that an apparent CFTR-dependent ENaC inhibition could be observed when resistance in series with the oocyte membrane was not low enough or the feedback voltage gain was not high enough. (PMID:15746174)
• IL-1b decreases expression of the ENaC alpha-subunit in alveolar epithelial cells via a p38 MAPK-dependent signaling pathway (PMID:15755725)
• These data show that alphaENaC expression is directly regulated by androgens in vitro and in vivo and highlight a potential mechanism explaining the reported gender differences in blood pressure. (PMID:16172422)
• forskolin induces human alphaENaC translocation in H441 lung epithelial cell monolayers (PMID:16373340)
• the interactions of delta-ENaC with alpha beta gamma-human epithelial sodium channel subunits could account for heterogeneity of native epithelial channels (PMID:16423824)
• analysis of the first membrane-spanning segment of the epithelial sodium channel (PMID:16912051)
• Incubation with glucose, the Ca2+-ionophore ionomycin and the cytokine TGF-beta1 were all found to evoke significant and time-dependent increases in both SGK1 and alphaENaC protein expression. (PMID:17170520)
• 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)
• ENaC alpha-subunit expression is inhibited by ENaC alpha-subunit in lung epithelial cells (PMID:17537777)
• data suggest casein kinase 1(CK1), & perhaps specifically CK1delta, regulates intracellular trafficking of alpha-A663T functional polymorphism of hENaC indirectly by altering rate of alpha-T663-hENaC biosynthesis and/or delivery to the plasma membrane (PMID:17596527)
• 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)
• Relative expression levels of alpha-subunit variants in four human lung epithelial cell lines, is examined. (PMID:17905853)
• EIPA [5-(N-ethyl-N-isopropyl)-amiloride hydrochloride] inhibition of ENaCs, possibly ENaC-alpha and ENaC-delta, significantly improved the sperm motility in healthy donors and in asthenospermia patients. (PMID:18298571)
• In CD, macroscopically noninflamed colon contributes to diarrhea via impaired ENaC-mediated sodium absorption. Inhibition of extracellular signal-regulated kinase might serve as a potential therapeutic strategy for CD diarrhea. (PMID:18355814)
• The novel mutation S562P is causing systemic pseudohypoaldosteronism type I in the homozygous state. Heterozygote SCNN1A mutation carriers revealed increased sweat sodium and chloride levels consistent with a dominant effect of the mutant S562P allele. (PMID:18547339)
• Results demonstrate genotype-phenotype relationships in pseudohypoaldosteronism, where ENaC function is correlated with the renin-aldosterone system and urinary Na/K ratios. (PMID:18634878)
• Human trophoblast BeWo cells express ENaC alpha subunit; aldosterone modulates a selective response by generating amiloride-sensitive sodium currents similar to those observed in other human tissues. (PMID:18665318)
• The distribution of genotype and allele frequencies of G2139A, A334T and A663T did not differ significantly between hypertensive subjects and control subjects in both Kazak and Uyghur populations (PMID:18703878)
• HEXIM1 may participate in tissue-selective determination of glucocorticoid sensitivity via direct interaction with GR at least in certain gene sets including atp1a1 and scnn1a. (PMID:18801933)
• 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)
• 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 more than three-fold significant increase in incidence of several rare ENaC polymorphisms was found in the patient group (30% vs. 9% in controls), indicating an involvement of ENaC in some patients by a polygenetic mechanism. (PMID:19462466)
• SPLUNC1 is secreted onto mucosal surfaces as a soluble volume sensor whose concentration and dilution can regulate ENaC activity and mucosal volumes, including that of airway surface liquid. (PMID:19541605)
• 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)
• the SGK1/Nedd4-2 signaling pathway regulates both CFTR and ENaC trafficking in CF epithelial cells (PMID:19617352)
• Glucocorticoids can activate the alpha-ENaC gene promoter independently of SGK1. (PMID:19619128)
• One or more copies of the variant C allele of SCNN1A rs5742912 was associated with an increased metabolic syndrome risk among female users of hormone replacement therapy. (PMID:19619703)
• 18% of cohort carried at least one missense mutation in ENaCalpha and 3 were transheterozygotes for CFTR/ENaCalpha (PMID:19720813)

Cross-species orthologs

26 orthologs

Organism	Symbol	Gene ID
mus_musculus	Scnn1a	ENSMUSG00000030340
rattus_norvegicus	Scnn1a	ENSRNOG00000019368
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), SCNN1D (ENSG00000162572), SCNN1G (ENSG00000166828), SCNN1B (ENSG00000168447), ASIC3 (ENSG00000213199), ASIC5 (ENSG00000256394)

Protein

Protein identifiers

Epithelial sodium channel subunit alpha — P37088 (reviewed: P37088)

Alternative names: Alpha-NaCH, Amiloride-sensitive sodium channel subunit alpha, Nonvoltage-gated sodium channel 1 subunit alpha, SCNEA, Sodium channel epithelial 1 subunit alpha

All UniProt accessions (5): C5HTZ1, P37088, F5GXE6, F5H5F8, J3KPV6

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. Not functional.

Subunit / interactions. Heterotrimer; containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit. Interacts with WWP1 (via WW domains). Interacts with WWP2 (via WW domains); inhibits the channel. Interacts with BPIFA1; the interaction is indirect via SCNN1B and inhibits the proteolytic processing of SCNN1A and SCNN1G and the activation of ENaC. Interacts with the full-length immature form of PCSK9 (pro-PCSK9); inhibits ENaC by promoting its proteasomal degradation.

Subcellular location. Apical cell membrane. Cell projection. Cilium. Cytoplasmic granule. Cytoplasm. Cytoplasmic vesicle. Secretory vesicle. Acrosome. Flagellum.

Tissue specificity. Expressed in the female reproductive tract, from the fimbrial end of the fallopian tube to the endometrium (at protein level). Expressed in kidney (at protein level). In the respiratory tract, expressed in the bronchial epithelium (at protein level). Highly expressed in lung. Detected at intermediate levels in pancreas and liver, and at low levels in heart and placenta. in skin, expressed in keratinocytes, melanocytes and Merkel cells of the epidermal sub-layers, stratum basale, stratum spinosum and stratum granulosum (at protein level). Expressed in the outer root sheath of the hair follicles (at protein level). Detected in both peripheral and central cells of the sebaceous gland (at protein level). Expressed by eccrine sweat glands (at protein level). In skin, also expressed by arrector pili muscle cells and intradermal adipocytes. Isoform 1 and isoform 2 predominate in all tissues. Detected in lung and heart.

Post-translational modifications. 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 SCNN1A subunit, 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.

Disease relevance. Pseudohypoaldosteronism 1B1, autosomal recessive (PHA1B1) [MIM:264350] 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. The degree of channel function impairment differentially affects the renin-aldosterone system and urinary Na/K ratios, resulting in distinct genotype-phenotype relationships in PHA1 patients. Loss-of-function mutations are associated with a severe clinical course and age-dependent hyperactivation of the renin-aldosterone system. This feature is not observed in patients with missense mutations that reduce but do not eliminate channel function. Markedly reduced channel activity results in impaired linear growth and delayed puberty. Bronchiectasis with or without elevated sweat chloride 2 (BESC2) [MIM:613021] 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. Liddle syndrome 3 (LIDLS3) [MIM:618126] 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.

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

Induction. By aldosterone.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. No significant expression or activity detected. No significant expression detected and not functional.

Similarity. Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1A subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
P37088-1	1, Alpha ENAC1	yes
P37088-2	2, Alpha ENAC2
P37088-3	3, Alpha ENACx
P37088-4	4, Alpha ENAC-19
P37088-5	5, Alpha ENAC+22
P37088-6	6

RefSeq proteins (3): NP_001029, NP_001153047, NP_001153048 (=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 (78 total): strand 22, sequence variant 12, disulfide bond 10, helix 8, splice variant 6, turn 4, topological domain 3, region of interest 3, compositionally biased region 2, site 2, transmembrane region 2, mutagenesis site 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6WTH	ELECTRON MICROSCOPY	3.06
6BQN	ELECTRON MICROSCOPY	3.9
2M3O	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P37088-F1	75.66	0.40

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): 178–179 (cleavage by furin); 204–205 (cleavage by furin)

Disulfide bonds (10): 133–305, 229–236, 282–289, 394–479, 416–475, 416–456, 420–471, 429–479, 429–456, 431–445

Mutagenesis-validated functional residues (2):

Position	Phenotype
394	increased channel activity.
644	prevents 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: 447 (showing top): FXR_IR1_Q6, MODULE_416, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, KOBAYASHI_EGFR_SIGNALING_24HR_UP, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, MODULE_64, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOCC_CELL_SURFACE

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 (4): ligand-gated sodium channel activity (GO:0015280), WW domain binding (GO:0050699), sodium channel activity (GO:0005272), protein binding (GO:0005515)

GO Cellular Component (15): acrosomal vesicle (GO:0001669), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), apical plasma membrane (GO:0016324), motile cilium (GO:0031514), sodium channel complex (GO:0034706), ciliary membrane (GO:0060170), extracellular exosome (GO:0070062), sperm principal piece (GO:0097228), cilium (GO:0005929), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

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	5
sensory perception of taste	2
cytoplasm	2
cilium	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
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
secretory granule	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
plasma membrane	1

Protein interactions and networks

STRING

1163 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCNN1A	SCNN1B	P51168	949
SCNN1A	NEDD4L	Q96PU5	885
SCNN1A	SLC12A3	P55017	857
SCNN1A	SCNN1G	P51170	849
SCNN1A	CFTR	P13569	819
SCNN1A	NEDD4	P46934	795
SCNN1A	WNK4	Q96J92	745
SCNN1A	NR3C2	P08235	744
SCNN1A	REN	P00797	742
SCNN1A	WNK1	P54963	732
SCNN1A	SGK1	O00141	717
SCNN1A	KCNJ1	P48048	707
SCNN1A	SLC12A1	Q13621	668
SCNN1A	PRSS8	Q16651	657
SCNN1A	SLC9A3	P48764	637

IntAct

47 interactions, top by confidence:

A	B	Type	Score
NEDD4	SCNN1A	psi-mi:“MI:0407”(direct interaction)	0.680
SCNN1G	SCNN1A	psi-mi:“MI:0915”(physical association)	0.640
PON2	NPC1	psi-mi:“MI:0914”(association)	0.530
FUT1	NDUFS4	psi-mi:“MI:0914”(association)	0.530
SCNN1A	SCNN1B	psi-mi:“MI:0915”(physical association)	0.490
SCNN1A	SCNN1D	psi-mi:“MI:0915”(physical association)	0.400
CLEC2D	ESYT2	psi-mi:“MI:0914”(association)	0.350
GP9	ESYT2	psi-mi:“MI:0914”(association)	0.350
APOM	ESYT2	psi-mi:“MI:0914”(association)	0.350
CLEC4E	ESYT2	psi-mi:“MI:0914”(association)	0.350
CHRNA1	ESYT2	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-DPB1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-G	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
CD3E	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-DQA1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
NRG1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-DRB1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
NCR3	POTEF	psi-mi:“MI:0914”(association)	0.350
DNAJB9	POTEF	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	ZNF316	psi-mi:“MI:0914”(association)	0.350
SIGLECL1	ELAPOR2	psi-mi:“MI:0914”(association)	0.350
ITM2C		psi-mi:“MI:0914”(association)	0.350
PDGFRA	QSOX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (90): USP8 (Affinity Capture-Western), LHS1 (Affinity Capture-Western), HYOU1 (Affinity Capture-Western), NEDD4L (Affinity Capture-Western), SCNN1A (Co-crystal Structure), SCNN1A (Reconstituted Complex), SCNN1A (Affinity Capture-Western), DERL1 (Affinity Capture-Western), SCNN1A (Affinity Capture-Western), SCNN1B (Affinity Capture-Western), SCNN1G (Affinity Capture-Western), SCNN1A (Affinity Capture-RNA), SCNN1A (Protein-peptide), SCNN1A (Affinity Capture-Western), SCNN1A (Reconstituted Complex)

ESM2 similar proteins: A1A5B4, A2A259, A2AIR5, E9PTA2, F6RG56, H2Q5A1, O35245, O62826, O70212, O94759, P02715, P04758, P09690, P11230, P13536, P23979, P25109, P35563, P37088, Q04671, Q13507, Q13563, Q4GZT3, Q60HE8, Q6IVV8, Q7Z403, Q86V40, Q8BWC0, Q8MIQ9, Q8R4F0, Q8TCT7, Q8TCU5, Q8TDD5, Q91YD4, Q96BD0, Q99J21, Q9EQJ0, Q9GZU1, Q9HA82, Q9JJH7

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

10 interactions.

A	Effect	B	Mechanism
MLLT3	“down-regulates quantity by repression”	SCNN1A	“transcriptional regulation”
dexamethasone	up-regulates	SCNN1A
IL1B	“down-regulates quantity by repression”	SCNN1A	“transcriptional regulation”
NEDD4L	“down-regulates quantity by destabilization”	SCNN1A	ubiquitination
SP1	“up-regulates quantity by expression”	SCNN1A	“transcriptional regulation”
SP3	“up-regulates quantity by expression”	SCNN1A	“transcriptional regulation”
TNF	“down-regulates quantity by repression”	SCNN1A	“transcriptional regulation”
SCNN1A	“up-regulates activity”	CACNA1H	binding
SCNN1A	“up-regulates quantity”	sodium(1+)	relocalization
HMGA2	“down-regulates quantity by repression”	SCNN1A	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Translocation of ZAP-70 to Immunological synapse	5	70.5×	1e-06
Phosphorylation of CD3 and TCR zeta chains	5	60.4×	1e-06
Co-inhibition by PD-1	5	57.7×	1e-06
Generation of second messenger molecules	5	38.5×	8e-06
Downstream TCR signaling	5	14.3×	6e-04
Interferon gamma signaling	5	13.9×	6e-04
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	6	11.6×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
adaptive immune response	7	9.8×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	15
Uncertain significance	241
Likely benign	71
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070290	NM_001038.6(SCNN1A):c.754del (p.Tyr252fs)	Pathogenic
1526188	NM_001038.6(SCNN1A):c.1360+2T>G	Pathogenic
2137293	NM_001038.6(SCNN1A):c.166C>T (p.Arg56Ter)	Pathogenic
2500734	NM_001038.6(SCNN1A):c.148del (p.Glu50fs)	Pathogenic
2735799	NM_001038.6(SCNN1A):c.1305del (p.Tyr436fs)	Pathogenic
3024263	NM_001038.6(SCNN1A):c.1361-3C>G	Pathogenic
3338298	NM_001038.6(SCNN1A):c.552_553insT (p.Pro185fs)	Pathogenic
3575087	NM_001038.6(SCNN1A):c.1474C>T (p.Arg492Ter)	Pathogenic
3575134	NM_001038.6(SCNN1A):c.505_506del (p.Thr169fs)	Pathogenic
4733533	NM_001038.6(SCNN1A):c.1332dup (p.Cys445fs)	Pathogenic
4735798	NM_001038.6(SCNN1A):c.285del (p.Phe95fs)	Pathogenic
4761737	NM_001038.6(SCNN1A):c.1520C>A (p.Ser507Ter)	Pathogenic
4770926	NM_001038.6(SCNN1A):c.885_886del (p.His296fs)	Pathogenic
4805249	NM_001038.6(SCNN1A):c.1374_1375del (p.Tyr458_Lys459delinsTer)	Pathogenic
802814	NM_001038.6(SCNN1A):c.1221_1227dup (p.Lys410fs)	Pathogenic
871275	NM_001038.6(SCNN1A):c.875+2dup	Pathogenic
9263	NM_001038.6(SCNN1A):c.203_204del (p.Ile68fs)	Pathogenic
9265	NM_001038.6(SCNN1A):c.1449del (p.Tyr484fs)	Pathogenic
9266	NM_001038.6(SCNN1A):c.729del (p.Val245fs)	Pathogenic
9270	NM_001038.6(SCNN1A):c.241C>T (p.Arg81Cys)	Pathogenic
988230	NM_001038.6(SCNN1A):c.574del (p.Arg192fs)	Pathogenic
992425	NM_001038.6(SCNN1A):c.1361-2A>G	Pathogenic
1049528	NM_001038.6(SCNN1A):c.1439+1G>T	Likely pathogenic
1704354	NM_001038.6(SCNN1A):c.655dup (p.Trp219fs)	Likely pathogenic
1810232	NM_001038.6(SCNN1A):c.604C>T (p.Arg202Ter)	Likely pathogenic
3061103	NM_001038.6(SCNN1A):c.875+3_875+6del	Likely pathogenic
3382271	NM_001038.6(SCNN1A):c.799_800del (p.Leu267fs)	Likely pathogenic
3575109	NM_001038.6(SCNN1A):c.979+1G>A	Likely pathogenic
3575110	NM_001038.6(SCNN1A):c.979G>T (p.Gly327Cys)	Likely pathogenic
3575118	NM_001038.6(SCNN1A):c.685-1G>A	Likely pathogenic

SpliceAI

2021 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6348250:CCAT:C	acceptor_gain	1.0000
12:6348251:CAT:C	acceptor_gain	1.0000
12:6348251:CATC:C	acceptor_gain	1.0000
12:6348253:TC:T	acceptor_loss	1.0000
12:6348254:C:CC	acceptor_gain	1.0000
12:6348254:CT:C	acceptor_loss	1.0000
12:6348808:G:GC	acceptor_gain	1.0000
12:6348810:G:GC	acceptor_gain	1.0000
12:6348816:C:CT	acceptor_gain	1.0000
12:6348817:A:T	acceptor_gain	1.0000
12:6348822:G:C	acceptor_gain	1.0000
12:6348822:G:GC	acceptor_gain	1.0000
12:6348945:CTGA:C	donor_loss	1.0000
12:6348946:TGA:T	donor_loss	1.0000
12:6348947:GA:G	donor_loss	1.0000
12:6348948:A:AG	donor_loss	1.0000
12:6348949:CCT:C	donor_gain	1.0000
12:6349001:CATTC:C	acceptor_gain	1.0000
12:6349002:ATTC:A	acceptor_gain	1.0000
12:6349003:TTC:T	acceptor_gain	1.0000
12:6349003:TTCC:T	acceptor_loss	1.0000
12:6349004:TC:T	acceptor_gain	1.0000
12:6349005:CC:C	acceptor_gain	1.0000
12:6349006:C:CA	acceptor_loss	1.0000
12:6349006:C:CC	acceptor_gain	1.0000
12:6349218:CACG:C	acceptor_gain	1.0000
12:6349220:CG:C	acceptor_gain	1.0000
12:6349222:C:CC	acceptor_gain	1.0000
12:6349404:CC:C	acceptor_gain	1.0000
12:6349405:CC:C	acceptor_gain	1.0000

AlphaMissense

4392 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6349342:C:G	C475S	0.996
12:6349343:A:T	C475S	0.996
12:6354551:C:G	C416S	0.996
12:6354552:A:G	C416R	0.996
12:6354552:A:T	C416S	0.996
12:6348211:A:G	W558R	0.995
12:6348211:A:T	W558R	0.995
12:6348220:A:G	W555R	0.995
12:6348220:A:T	W555R	0.995
12:6354550:A:C	C416W	0.995
12:6354551:C:T	C416Y	0.995
12:6362173:C:A	W251C	0.995
12:6362173:C:G	W251C	0.995
12:6362175:A:G	W251R	0.995
12:6362175:A:T	W251R	0.995
12:6374385:G:C	C133W	0.995
12:6349182:C:A	W493C	0.994
12:6349182:C:G	W493C	0.994
12:6349184:A:G	W493R	0.994
12:6349184:A:T	W493R	0.994
12:6349354:C:G	C471S	0.994
12:6349355:A:T	C471S	0.994
12:6354811:C:G	C394S	0.994
12:6354812:A:T	C394S	0.994
12:6374386:C:T	C133Y	0.994
12:6348215:G:C	S556R	0.993
12:6348215:G:T	S556R	0.993
12:6348217:T:G	S556R	0.993
12:6349343:A:G	C475R	0.993
12:6354439:C:A	W453C	0.993

dbSNP variants (sampled 300 via entrez): RS1000334477 (12:6352143 T>C), RS1000342512 (12:6352605 G>T), RS1000420080 (12:6378435 G>A,T), RS1000583869 (12:6347201 G>A), RS1000703018 (12:6347372 C>A,G), RS1000885973 (12:6362032 C>T), RS1000904281 (12:6355657 C>A,T), RS1000957562 (12:6361738 C>T), RS1001034416 (12:6363068 C>T), RS1001146266 (12:6367193 G>A), RS1001252865 (12:6368007 T>C), RS1001253121 (12:6356045 A>C), RS1001330976 (12:6369220 G>A,T), RS1001348690 (12:6356888 A>G), RS1001425567 (12:6368530 C>A,G,T)

Disease associations

OMIM: gene MIM:600228 | disease phenotypes: MIM:264350, MIM:613021, MIM:618126, MIM:252270, MIM:601144

GenCC curated gene-disease

Disease	Classification	Inheritance
pseudohypoaldosteronism, type IB1, autosomal recessive	Definitive	Autosomal recessive
bronchiectasis with or without elevated sweat chloride 2	Moderate	Autosomal dominant
Brugada syndrome	Supportive	Autosomal dominant
Liddle syndrome	Supportive	Autosomal dominant
Liddle syndrome 3	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
pseudohypoaldosteronism, type IB1, autosomal recessive	Strong	AR

Mondo (10): pseudohypoaldosteronism, type IB1, autosomal recessive (MONDO:0009917), bronchiectasis with or without elevated sweat chloride 2 (MONDO:0013087), Liddle syndrome 3 (MONDO:0029132), prostate cancer (MONDO:0008315), monosomy 7 myelodysplasia and leukemia syndrome 1 (MONDO:0009646), Brugada syndrome 1 (MONDO:0011001), idiopathic bronchiectasis (MONDO:0018956), pseudohypoaldosteronism (MONDO:0018638), Brugada syndrome (MONDO:0015263), Liddle syndrome (MONDO:0008323)

Orphanet (6): Generalized pseudohypoaldosteronism type 1 (Orphanet:171876), Idiopathic bronchiectasis (Orphanet:60033), Pseudohypoaldosteronism type 1 (Orphanet:756), Familial prostate cancer (Orphanet:1331), Brugada syndrome (Orphanet:130), Pseudohypoaldosteronism (Orphanet:444916)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000112	Nephropathy
HP:0000127	Renal salt wasting
HP:0000822	Hypertension
HP:0000841	Hyperactive renin-angiotensin system
HP:0000848	Increased circulating renin concentration
HP:0000859	Increased circulating aldosterone concentration
HP:0001047	Atopic dermatitis
HP:0001081	Cholelithiasis
HP:0001217	Clubbing
HP:0001279	Syncope
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001531	Failure to thrive in infancy
HP:0001649	Tachycardia
HP:0001658	Myocardial infarction
HP:0001663	Ventricular fibrillation
HP:0001695	Cardiac arrest
HP:0001824	Weight loss
HP:0001942	Metabolic acidosis
HP:0001944	Dehydration
HP:0001945	Fever
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002019	Constipation
HP:0002094	Dyspnea
HP:0002097	Emphysema
HP:0002105	Hemoptysis

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001957_10	Obesity (early onset extreme)	3.000000e-07
GCST004865_7	Itch intensity from mosquito bite adjusted by bite size	5.000000e-08
GCST004866_8	Alopecia areata	8.000000e-06
GCST005581_33	Primary biliary cirrhosis	2.000000e-16
GCST005581_34	Primary biliary cirrhosis	7.000000e-19
GCST005581_7	Primary biliary cirrhosis	1.000000e-14
GCST005581_8	Primary biliary cirrhosis	2.000000e-09
GCST009028_11	Adverse response to drug	6.000000e-07
GCST90016667_7	Spleen volume	1.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0009658	adverse effect

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
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
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D011546	Pseudohypoaldosteronism	C12.050.351.968.419.815.770; C12.200.777.419.815.770; C12.950.419.815.770; C16.320.831.770
C567813	Bronchiectasis With Or Without Elevated Sweat Chloride 2 (supp.)
C565370	Monosomy 7 of Bone Marrow (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1791 (SINGLE PROTEIN), CHEMBL2107836 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 63,913 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL945	AMILORIDE	4	63,705
CHEMBL212432	552-02 FREE BASE	2	208

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Epithelial sodium channel (ENaC)

ChEMBL bioactivities

43 potent at pChembl≥5 of 43 total, top 43 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.15	IC50	7	nM	CHEMBL212531
8.15	IC50	7	nM	CHEMBL212431
8.10	IC50	8	nM	552-02 FREE BASE
8.05	IC50	9	nM	CHEMBL209303
8.05	IC50	9	nM	CHEMBL211161
7.85	IC50	14	nM	CHEMBL214239
7.82	IC50	15	nM	CHEMBL377986
7.77	IC50	17	nM	CHEMBL211600
7.77	IC50	17	nM	CHEMBL210876
7.77	IC50	17	nM	CHEMBL5303508
7.70	IC50	20	nM	CHEMBL379433
7.70	IC50	20	nM	CHEMBL380011
7.68	IC50	21	nM	CHEMBL386222
7.68	IC50	21	nM	CHEMBL212410
7.66	IC50	22	nM	CHEMBL379756
7.60	IC50	25	nM	CHEMBL214220
7.58	IC50	26	nM	CHEMBL212534
7.55	IC50	28	nM	CHEMBL211658
7.54	IC50	29	nM	CHEMBL209659
7.52	IC50	30	nM	CHEMBL379066
7.51	IC50	31	nM	CHEMBL208889
7.50	IC50	32	nM	CHEMBL211946
7.39	IC50	41	nM	CHEMBL211773
7.38	IC50	42	nM	CHEMBL211072
7.32	IC50	48	nM	CHEMBL209017
7.30	IC50	50	nM	CHEMBL211664
7.29	IC50	51	nM	CHEMBL213175
7.24	IC50	58	nM	CHEMBL208620
7.21	IC50	62	nM	CHEMBL209977
7.19	IC50	64	nM	CHEMBL211221
7.18	IC50	66	nM	CHEMBL211611
7.18	IC50	66	nM	BENZAMIL
7.17	IC50	68	nM	CHEMBL377239
7.14	IC50	73	nM	CHEMBL380393
7.11	IC50	77	nM	CHEMBL209104
7.06	IC50	88	nM	CHEMBL211793
7.06	IC50	87	nM	CHEMBL210966
6.97	IC50	107	nM	CHEMBL377688
6.97	IC50	108	nM	CHEMBL210981
6.91	IC50	124	nM	CHEMBL210967
6.40	IC50	401	nM	PHENAMIL
6.32	IC50	477	nM	CHEMBL210866
6.11	IC50	776	nM	AMILORIDE

PubChem BioAssay actives

42 with measured affinity, of 56 total; 42 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3,5-diamino-6-chloro-N-[N’-[4-[4-(3-hydroxypropoxy)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0070	uM
3,5-diamino-6-chloro-N-[N’-[4-[4-[(2S)-2,3-dihydroxypropoxy]phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0070	uM
3,5-diamino-6-chloro-N-[N’-[4-[4-(2,3-dihydroxypropoxy)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0080	uM
3,5-diamino-6-chloro-N-[N’-[4-[4-[(2R)-2,3-dihydroxypropoxy]phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0090	uM
3,5-diamino-6-chloro-N-[N’-[4-[4-(2-hydroxyethoxy)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0090	uM
3,5-diamino-6-chloro-N-[N’-[4-[4-(hydroxymethyl)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0140	uM
3,5-diamino-6-chloro-N-[N’-[4-(4-methoxyphenyl)butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0150	uM
3,5-diamino-6-chloro-N-[N’-[4-[3-(2-hydroxyethoxy)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0170	uM
3,5-diamino-6-chloro-N-[N’-[4-(4-hydroxyphenyl)butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0170	uM
3-[4-[4-[[amino-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]methylidene]amino]butyl]phenoxy]propanoic acid	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0200	uM
3,5-diamino-6-chloro-N-[N’-[4-(3-hydroxyphenyl)butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0200	uM
3,5-diamino-N-[N’-[4-(4-aminophenyl)butyl]carbamimidoyl]-6-chloropyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0210	uM
4-[4-[[amino-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]methylidene]amino]butyl]benzenesulfonic acid	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0210	uM
methyl 4-[4-[[amino-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]methylidene]amino]butyl]benzoate	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0220	uM
3,5-diamino-6-chloro-N-[N’-[3-(4-methoxyphenoxy)propyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0250	uM
3,5-diamino-6-chloro-N-[N’-[4-[3-(2,3-dihydroxypropoxy)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0260	uM
3,5-diamino-6-chloro-N-[N’-[4-[2-(2,3-dihydroxypropoxy)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0280	uM
3,5-diamino-6-chloro-N-[N’-(4-phenylbutyl)carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0290	uM
3,5-diamino-6-chloro-N-[N’-[4-(2-hydroxyphenyl)butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0300	uM
3,5-diamino-6-chloro-N-[N’-[4-[2-(2-hydroxyethoxy)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0310	uM
3,5-diamino-6-chloro-N-[N’-[3-(4-hydroxyphenoxy)propyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0320	uM
3,5-diamino-6-chloro-N-[N’-[2-[(4-methoxyphenyl)methoxy]ethyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0410	uM
3,5-diamino-6-chloro-N-[N’-[4-(3,4-dihydroxyphenyl)butyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0420	uM
2-[4-[4-[[amino-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]methylidene]amino]butyl]phenoxy]acetic acid	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0480	uM
3,5-diamino-6-chloro-N-[N’-(3-phenylpropyl)carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0500	uM
4-[4-[[amino-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]methylidene]amino]butyl]benzoic acid	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0510	uM
3,5-diamino-6-chloro-N-[N’-(6-phenylhexyl)carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0580	uM
3,5-diamino-6-chloro-N-[N’-[2-(4-hydroxyphenyl)ethyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0620	uM
3,5-diamino-6-chloro-N-[N’-[5-(4-hydroxyphenyl)pentyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0640	uM
3,5-diamino-N-(N’-benzylcarbamimidoyl)-6-chloropyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0660	uM
3,5-diamino-6-chloro-N-[N’-(2-phenylethyl)carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0660	uM
3,5-diamino-6-chloro-N-[N’-(5-phenylpentyl)carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0680	uM
(2S,3S,4S,5R)-6-[4-[4-[[amino-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]methylidene]amino]butyl]phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0730	uM
3,5-diamino-6-chloro-N-[N’-[5-(4-methoxyphenyl)pentyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0770	uM
3,5-diamino-6-chloro-N-(N’-hexylcarbamimidoyl)pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0870	uM
3,5-diamino-6-chloro-N-[N’-[3-(4-hydroxyphenyl)propyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.0880	uM
3,5-diamino-6-chloro-N-[N’-(2-hydroxyethyl)carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.1070	uM
3,5-diamino-6-chloro-N-(N’-octylcarbamimidoyl)pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.1080	uM
3,5-diamino-6-chloro-N-[N’-[3-(4-methoxyphenyl)propyl]carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.1240	uM
3,5-diamino-6-chloro-N-(N’-phenylcarbamimidoyl)pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.4010	uM
3,5-diamino-6-chloro-N-[N’-(8-phenyloctyl)carbamimidoyl]pyrazine-2-carboxamide	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.4770	uM
Amiloride	268105: Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	ic50	0.7760	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	6
trichostatin A	increases expression, affects cotreatment	3
Air Pollutants	increases expression, decreases expression, increases abundance	3
Amiloride	affects binding, decreases reaction, increases transport, decreases activity	3
Benzo(a)pyrene	increases expression, decreases methylation	3
Estradiol	affects expression, affects cotreatment, increases expression	3
Sodium	decreases reaction, increases transport, affects transport, affects binding	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Particulate Matter	decreases reaction, increases expression, decreases expression, increases abundance	3
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Ethanol	affects cotreatment, increases expression	2
Aldosterone	affects expression, increases expression	2
Cisplatin	increases expression, affects expression, affects cotreatment	2
Progesterone	affects expression, decreases expression	2
Silicon Dioxide	decreases expression, decreases methylation	2
Tretinoin	decreases expression, increases expression	2
3,19-(2-bromobenzylidene)andrographolide	decreases response to substance, increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	decreases expression	1
beta-lapachone	decreases expression	1
sulforaphane	decreases expression	1
butyraldehyde	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 4 binding, 1 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4200634	ADMET	Inhibition of S-3969-stimulated recombinant human ENaC alpha 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
CHEMBL868533	Binding	Inhibition of dog bronchi prototypical epithelial sodium channel by electrophysiological assay	Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: drugs for cystic fibrosis and chronic bronchitis. — J Med Chem
CHEMBL5304011	Functional	Inhibition of Na+ current by Ussing Chamber	Data for DCP probe BI-8668

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer