pseudohypoaldosteronism, type IB1, autosomal recessive

Summary

pseudohypoaldosteronism, type IB1, autosomal recessive (MONDO:0009917) is a disease caused by variants in SCNN1A, SCNN1B, and SCNN1G, with 4 cohort genes and 1 clinical trial. The dominant Reactome pathway is Sensory perception of salty taste (3 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (United Kingdom) [Orphanet-validated]
• Causal genes: SCNN1A (GenCC Definitive), SCNN1B (GenCC Strong), SCNN1G (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 372
• Phenotypes (HPO): 22
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.6	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000848	Increased circulating renin level	Very frequent (80-99%)
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0002153	Hyperkalemia	Very frequent (80-99%)
HP:0002902	Hyponatremia	Very frequent (80-99%)
HP:0011740	Glucocortocoid-insensitive primary hyperaldosteronism	Very frequent (80-99%)
HP:0040085	Abnormal circulating aldosterone	Very frequent (80-99%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001944	Dehydration	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0031274	Hypovolemic shock	Frequent (30-79%)
HP:0200117	Recurrent upper and lower respiratory tract infections	Frequent (30-79%)
HP:0001047	Atopic dermatitis	Occasional (5-29%)
HP:0001081	Cholelithiasis	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002754	Osteomyelitis	Occasional (5-29%)
HP:0003508	Proportionate short stature	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0011110	Recurrent tonsillitis	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0012735	Cough	Occasional (5-29%)
HP:0030828	Wheezing	Occasional (5-29%)
HP:0200039	Pustule	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoaldosteronism, type IB1, autosomal recessive
Mondo ID	MONDO:0009917
OMIM	264350
Orphanet	171876
UMLS	C5774176
MedGen	1823950
GARD	0004552
Is cancer (heuristic)	no

Also known as: autosomal recessive PHA 1 · autosomal recessive pseudohypoaldosteronism type 1 · generalised PHA1 · generalised pseudohypoaldosteronism type 1 · generalized PHA1 · generalized pseudohypoaldosteronism type 1 · PHA1B · pseudohypoaldosteronism type 1 autosomal recessive · pseudohypoaldosteronism type 1, recessive · pseudohypoaldosteronism, type I, autosomal recessive

Data availability: 372 ClinVar variants · 11 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubule disorder › inherited renal tubular disease › pseudohypoaldosteronism type 1 › pseudohypoaldosteronism, type IB1, autosomal recessive

Related subtypes (3): autosomal dominant pseudohypoaldosteronism type 1, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive

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

372 retrieved; paginated sample, class counts are floors:

176 uncertain significance, 88 conflicting classifications of pathogenicity, 36 benign, 33 benign/likely benign, 14 pathogenic, 13 likely pathogenic, 10 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1526188	NM_001038.6(SCNN1A):c.1360+2T>G	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
2137293	NM_001038.6(SCNN1A):c.166C>T (p.Arg56Ter)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
2500734	NM_001038.6(SCNN1A):c.148del (p.Glu50fs)	SCNN1A	Pathogenic	criteria provided, single submitter
3024263	NM_001038.6(SCNN1A):c.1361-3C>G	SCNN1A	Pathogenic	criteria provided, single submitter
3338298	NM_001038.6(SCNN1A):c.552_553insT (p.Pro185fs)	SCNN1A	Pathogenic	criteria provided, single submitter
3575087	NM_001038.6(SCNN1A):c.1474C>T (p.Arg492Ter)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
3575134	NM_001038.6(SCNN1A):c.505_506del (p.Thr169fs)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
450202	NM_001038.6(SCNN1A):c.875+1G>A	SCNN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802813	NM_001038.6(SCNN1A):c.1439+1G>A	SCNN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802814	NM_001038.6(SCNN1A):c.1221_1227dup (p.Lys410fs)	SCNN1A	Pathogenic	criteria provided, single submitter
9263	NM_001038.6(SCNN1A):c.203_204del (p.Ile68fs)	SCNN1A	Pathogenic	criteria provided, single submitter
9265	NM_001038.6(SCNN1A):c.1449del (p.Tyr484fs)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
9266	NM_001038.6(SCNN1A):c.729del (p.Val245fs)	SCNN1A	Pathogenic	no assertion criteria provided
988230	NM_001038.6(SCNN1A):c.574del (p.Arg192fs)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
992425	NM_001038.6(SCNN1A):c.1361-2A>G	SCNN1A	Pathogenic	no assertion criteria provided
1341532	NM_000336.3(SCNN1B):c.539C>A (p.Ser180Ter)	SCNN1B	Pathogenic	criteria provided, single submitter
1704354	NM_001038.6(SCNN1A):c.655dup (p.Trp219fs)	SCNN1A	Likely pathogenic	criteria provided, single submitter
3382271	NM_001038.6(SCNN1A):c.799_800del (p.Leu267fs)	SCNN1A	Likely pathogenic	criteria provided, single submitter
3575109	NM_001038.6(SCNN1A):c.979+1G>A	SCNN1A	Likely pathogenic	criteria provided, single submitter
3575110	NM_001038.6(SCNN1A):c.979G>T (p.Gly327Cys)	SCNN1A	Likely pathogenic	criteria provided, single submitter
3575118	NM_001038.6(SCNN1A):c.685-1G>A	SCNN1A	Likely pathogenic	criteria provided, single submitter
3780584	NM_001038.6(SCNN1A):c.33dup (p.Ser12Ter)	SCNN1A	Likely pathogenic	criteria provided, single submitter
4845817	NM_001038.6(SCNN1A):c.-54-1G>A	SCNN1A	Likely pathogenic	criteria provided, single submitter
591450	NM_001038.6(SCNN1A):c.69del (p.Asn24fs)	SCNN1A	Likely pathogenic	criteria provided, single submitter
9267	NM_001038.6(SCNN1A):c.1685C>T (p.Ser562Leu)	SCNN1A	Likely pathogenic	criteria provided, single submitter
488409	NM_000336.3(SCNN1B):c.1074C>A (p.Tyr358Ter)	SCNN1B	Likely pathogenic	no assertion criteria provided
8838	NM_000336.3(SCNN1B):c.800C>T (p.Pro267Leu)	SCNN1B	Likely pathogenic	criteria provided, single submitter
1120080	NM_001039.4(SCNN1G):c.1318C>T (p.Arg440Ter)	SCNN1G	Likely pathogenic	criteria provided, single submitter
804476	NM_001039.4(SCNN1G):c.142dup (p.Arg48fs)	SCNN1G	Likely pathogenic	criteria provided, single submitter
2206584	NM_001038.6(SCNN1A):c.1949G>A (p.Arg650His)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 29 · Orphanet: 10 · 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
SCNN1A	Definitive	Autosomal recessive	pseudohypoaldosteronism, type IB1, autosomal recessive	12
SCNN1B	Definitive	Autosomal recessive	pseudohypoaldosteronism, type IB2, autosomal recessive	9
SCNN1G	Strong	Autosomal recessive	pseudohypoaldosteronism, type IB1, autosomal recessive	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCNN1A	Orphanet:130	Brugada syndrome
SCNN1A	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1A	Orphanet:526	Liddle syndrome
SCNN1A	Orphanet:60033	Idiopathic bronchiectasis
SCNN1B	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1B	Orphanet:526	Liddle syndrome
SCNN1B	Orphanet:60033	Idiopathic bronchiectasis
SCNN1G	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1G	Orphanet:526	Liddle syndrome
SCNN1G	Orphanet:60033	Idiopathic bronchiectasis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCNN1A	HGNC:10599	ENSG00000111319	P37088	Epithelial sodium channel subunit alpha	gencc,clinvar
SCNN1B	HGNC:10600	ENSG00000168447	P51168	Epithelial sodium channel subunit beta	gencc,clinvar
SCNN1G	HGNC:10602	ENSG00000166828	P51170	Epithelial sodium channel subunit gamma	gencc,clinvar
LTBR	HGNC:6718	ENSG00000111321	P36941	Tumor necrosis factor receptor superfamily member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCNN1A	Epithelial sodium channel subunit alpha	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.
SCNN1B	Epithelial sodium channel subunit beta	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.
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.
LTBR	Tumor necrosis factor receptor superfamily member 3	Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCNN1A	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
SCNN1B	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
SCNN1G	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
LTBR	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_3_LTBR, TNFRSF3_N

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	2
metanephros cortex	1
nasal cavity epithelium	1
right uterine tube	1
esophagus mucosa	1
rectum	1
bronchial epithelial cell	1
kidney epithelium	1
renal medulla	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCNN1A	283	broad	marker	nasal cavity epithelium, metanephros cortex, right uterine tube
SCNN1B	188	broad	marker	lower esophagus mucosa, esophagus mucosa, rectum
SCNN1G	133	broad	marker	renal medulla, kidney epithelium, bronchial epithelial cell
LTBR	250	ubiquitous	marker	lower esophagus mucosa, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LTBR	1,891
SCNN1A	1,300
SCNN1G	1,037
SCNN1B	1,013

Intra-cohort edges

A	B	Sources
SCNN1A	SCNN1B	biogrid_interaction, intact, string_interaction
SCNN1A	SCNN1G	biogrid_interaction, intact, string_interaction
SCNN1B	SCNN1G	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCNN1B	P51168	5
SCNN1G	P51170	5
SCNN1A	P37088	3
LTBR	P36941	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 evidence-associated genes (4 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 4 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	3	1427.5×	3e-09	SCNN1A, SCNN1B, SCNN1G
Sensory perception of taste	3	251.9×	4e-07	SCNN1A, SCNN1B, SCNN1G
Stimuli-sensing channels	3	102.0×	4e-06	SCNN1A, SCNN1B, SCNN1G
Ion channel transport	3	72.0×	7e-06	SCNN1A, SCNN1B, SCNN1G
Sensory Perception	3	71.4×	7e-06	SCNN1A, SCNN1B, SCNN1G
Transport of small molecules	3	18.9×	3e-04	SCNN1A, SCNN1B, SCNN1G
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	167.9×	0.007	LTBR
TNFR2 non-canonical NF-kB pathway	1	45.3×	0.022	LTBR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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	3	3159.8×	7e-10	SCNN1A, SCNN1B, SCNN1G
cellular response to aldosterone	3	1805.6×	3e-09	SCNN1A, SCNN1B, SCNN1G
cellular response to vasopressin	3	1579.9×	3e-09	SCNN1A, SCNN1B, SCNN1G
multicellular organismal-level water homeostasis	3	1263.9×	4e-09	SCNN1A, SCNN1B, SCNN1G
sensory perception of sour taste	3	1263.9×	4e-09	SCNN1A, SCNN1B, SCNN1G
sodium ion homeostasis	3	702.2×	2e-08	SCNN1A, SCNN1B, SCNN1G
intracellular sodium ion homeostasis	3	574.5×	4e-08	SCNN1A, SCNN1B, SCNN1G
cellular response to acidic pH	3	549.5×	4e-08	SCNN1A, SCNN1B, SCNN1G
sodium ion import across plasma membrane	3	468.1×	6e-08	SCNN1A, SCNN1B, SCNN1G
regulation of blood pressure	3	166.3×	1e-06	SCNN1A, SCNN1B, SCNN1G
sodium ion transmembrane transport	3	152.3×	1e-06	SCNN1A, SCNN1B, SCNN1G
hematopoietic or lymphoid organ development	1	4213.0×	7e-04	LTBR
aldosterone metabolic process	1	2106.5×	0.001	SCNN1B
leukocyte activation involved in inflammatory response	1	1404.3×	0.002	SCNN1B
neutrophil-mediated killing of bacterium	1	1053.2×	0.002	SCNN1B
epithelial fluid transport	1	526.6×	0.004	SCNN1B
neutrophil activation involved in immune response	1	468.1×	0.004	SCNN1B
artery smooth muscle contraction	1	468.1×	0.004	SCNN1B
erythrocyte homeostasis	1	324.1×	0.005	SCNN1B
mucus secretion	1	324.1×	0.005	SCNN1B
renal system process	1	280.9×	0.006	SCNN1B
myeloid dendritic cell differentiation	1	234.1×	0.007	LTBR
potassium ion homeostasis	1	191.5×	0.008	SCNN1B
response to food	1	123.9×	0.012	SCNN1B
positive regulation of extrinsic apoptotic signaling pathway	1	113.9×	0.012	LTBR
lung alveolus development	1	87.8×	0.015	SCNN1B
cellular response to mechanical stimulus	1	54.0×	0.024	LTBR
positive regulation of JNK cascade	1	40.9×	0.030	LTBR
multicellular organism growth	1	34.2×	0.035	SCNN1B
gene expression	1	20.0×	0.057	SCNN1B

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCNN1A	AMILORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCNN1A	2	4
SCNN1B	0	0
SCNN1G	0	0
LTBR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMILORIDE	4	SCNN1A
552-02 FREE BASE	2	SCNN1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCNN1A	6	Binding:4, ADMET:1, Functional:1
SCNN1B	5	Binding:3, ADMET:1, Functional:1
SCNN1G	5	Binding:3, ADMET:1, Functional:1
LTBR	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
AMILORIDE	4	SCNN1A
552-02 FREE BASE	2	SCNN1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCNN1A
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	3	SCNN1B, SCNN1G, LTBR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SCNN1B	5	SCNN1A
SCNN1G	5	—
LTBR	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases