Liddle syndrome 2

Summary

Liddle syndrome 2 (MONDO:0020854) is a disease caused by SCNN1G (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SCNN1G (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 173

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Liddle syndrome 2
Mondo ID	MONDO:0020854
OMIM	618114
UMLS	C4748251
MedGen	1648476
GARD	0025263
Is cancer (heuristic)	no

Also known as: Liddle syndrome 2 · Liddle syndrome caused by mutation in SCNN1G · LIDLS2 · SCNN1G Liddle syndrome

Data availability: 173 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Liddle syndrome › Liddle syndrome 2

Related subtypes (2): Liddle syndrome 1, Liddle syndrome 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

173 retrieved; paginated sample, class counts are floors:

112 uncertain significance, 24 benign, 22 conflicting classifications of pathogenicity, 8 benign/likely benign, 3 pathogenic, 2 likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
561163	NM_001039.4(SCNN1G):c.1699C>T (p.Gln567Ter)	SCNN1G	Pathogenic	no assertion criteria provided
565277	NM_001039.4(SCNN1G):c.1749_1753del (p.Glu583fs)	SCNN1G	Pathogenic	no assertion criteria provided
8824	NM_001039.4(SCNN1G):c.1718G>A (p.Trp573Ter)	SCNN1G	Pathogenic	no assertion criteria provided
3579896	NM_001039.4(SCNN1G):c.416_417del (p.Glu139fs)	SCNN1G	Likely pathogenic	criteria provided, single submitter
804476	NM_001039.4(SCNN1G):c.142dup (p.Arg48fs)	SCNN1G	Likely pathogenic	criteria provided, single submitter
1256591	NM_001039.4(SCNN1G):c.1939G>T (p.Asp647Tyr)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286685	NM_001039.4(SCNN1G):c.1575G>A (p.Glu525=)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2883968	NM_001039.4(SCNN1G):c.1550T>A (p.Met517Lys)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2956870	NM_001039.4(SCNN1G):c.1078-17TGC[3]	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318345	NM_001039.4(SCNN1G):c.-23G>A	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318346	NM_001039.4(SCNN1G):c.399G>A (p.Glu133=)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318349	NM_001039.4(SCNN1G):c.477G>A (p.Pro159=)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318350	NM_001039.4(SCNN1G):c.538C>T (p.Arg180Trp)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318353	NM_001039.4(SCNN1G):c.776C>A (p.Thr259Asn)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318354	NM_001039.4(SCNN1G):c.1083G>A (p.Glu361=)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318357	NM_001039.4(SCNN1G):c.1452C>A (p.Leu484=)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318359	NM_001039.4(SCNN1G):c.1589A>G (p.Asn530Ser)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318360	NM_001039.4(SCNN1G):c.1827G>C (p.Leu609Phe)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318366	NM_001039.4(SCNN1G):c.*328G>A	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318377	NM_001039.4(SCNN1G):c.*1147A>G	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318381	NM_001039.4(SCNN1G):c.*1370G>A	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451433	NM_001039.4(SCNN1G):c.1550T>C (p.Met517Thr)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808015	NM_001039.4(SCNN1G):c.1476A>G (p.Val492=)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885325	NM_001039.4(SCNN1G):c.*491G>A	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886034	NM_001039.4(SCNN1G):c.132C>T (p.Ile44=)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886156	NM_001039.4(SCNN1G):c.1861G>A (p.Gly621Ser)	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887172	NM_001039.4(SCNN1G):c.*230C>T	SCNN1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1185021	NM_001039.4(SCNN1G):c.1532T>A (p.Leu511Gln)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
1304028	NM_001039.4(SCNN1G):c.1874C>G (p.Pro625Arg)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
1313539	NM_001039.4(SCNN1G):c.470G>A (p.Arg157Gln)	SCNN1G	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SCNN1G	Strong	Autosomal dominant	Liddle syndrome 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCNN1G	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1G	Orphanet:526	Liddle syndrome
SCNN1G	Orphanet:60033	Idiopathic bronchiectasis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCNN1G	HGNC:10602	ENSG00000166828	P51170	Epithelial sodium channel subunit gamma	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCNN1G	Epithelial sodium channel subunit gamma	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCNN1G	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
kidney epithelium	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCNN1G	133	broad	marker	renal medulla, kidney epithelium, bronchial epithelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCNN1G	1,037

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCNN1G	P51170	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory perception of salty taste	1	1903.3×	0.003	SCNN1G
Sensory perception of taste	1	335.9×	0.009	SCNN1G
Stimuli-sensing channels	1	135.9×	0.013	SCNN1G
Ion channel transport	1	96.0×	0.013	SCNN1G
Sensory Perception	1	95.2×	0.013	SCNN1G
Transport of small molecules	1	25.1×	0.040	SCNN1G

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of salty taste	1	4213.0×	0.001	SCNN1G
cellular response to aldosterone	1	2407.4×	0.001	SCNN1G
cellular response to vasopressin	1	2106.5×	0.001	SCNN1G
multicellular organismal-level water homeostasis	1	1685.2×	0.001	SCNN1G
sensory perception of sour taste	1	1685.2×	0.001	SCNN1G
sodium ion homeostasis	1	936.2×	0.002	SCNN1G
intracellular sodium ion homeostasis	1	766.0×	0.002	SCNN1G
cellular response to acidic pH	1	732.7×	0.002	SCNN1G
sodium ion import across plasma membrane	1	624.1×	0.002	SCNN1G
regulation of blood pressure	1	221.7×	0.005	SCNN1G
sodium ion transmembrane transport	1	203.0×	0.005	SCNN1G

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCNN1G	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SCNN1G	5	Binding:3, ADMET:1, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SCNN1G

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SCNN1G	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.