pseudohypoaldosteronism type 2B

Summary

pseudohypoaldosteronism type 2B (MONDO:0013777) is a disease caused by WNK4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: WNK4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 282

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoaldosteronism type 2B
Mondo ID	MONDO:0013777
MeSH	C564161
OMIM	614491
Orphanet	88939
ICD-11	853594829
UMLS	C1840390
MedGen	374457
GARD	0016776
Is cancer (heuristic)	no

Also known as: PHA2B · pseudohypoaldosteronism type 2 caused by mutation in WNK4 · pseudohypoaldosteronism, type IIB · WNK4 pseudohypoaldosteronism type 2

Data availability: 282 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubular transport disease › pseudohypoaldosteronism › inherited pseudohypoaldosteronism › pseudohypoaldosteronism type 2 › pseudohypoaldosteronism type 2B

Related subtypes (4): pseudohypoaldosteronism type 2A, pseudohypoaldosteronism type 2C, pseudohypoaldosteronism type 2D, pseudohypoaldosteronism type 2E

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

282 retrieved; paginated sample, class counts are floors:

191 uncertain significance, 28 conflicting classifications of pathogenicity, 23 benign/likely benign, 20 benign, 11 likely benign, 4 not provided, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344664	NM_032387.5(WNK4):c.506C>T (p.Pro169Leu)	WNK4	Pathogenic	no assertion criteria provided
7660	NM_032387.5(WNK4):c.1693C>G (p.Gln565Glu)	WNK4	Pathogenic	criteria provided, single submitter
7662	NM_032387.5(WNK4):c.1691A>C (p.Asp564Ala)	WNK4	Pathogenic	no assertion criteria provided
1177431	NM_032387.5(WNK4):c.3108del (p.Thr1037fs)	WNK4	Likely pathogenic	criteria provided, single submitter
7661	NM_032387.5(WNK4):c.1684G>A (p.Glu562Lys)	WNK4	Likely pathogenic	criteria provided, single submitter
1116818	NM_032387.5(WNK4):c.1573C>G (p.Arg525Gly)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1698524	NM_032387.5(WNK4):c.1800del (p.Ala601fs)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2054849	NM_032387.5(WNK4):c.2893C>T (p.Leu965Phe)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2065989	NM_032387.5(WNK4):c.374C>G (p.Pro125Arg)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2159179	NM_032387.5(WNK4):c.1510C>T (p.Gln504Ter)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2355865	NM_032387.5(WNK4):c.2905G>A (p.Val969Ile)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2528888	NM_032387.5(WNK4):c.1459G>A (p.Glu487Lys)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2699785	NM_032387.5(WNK4):c.2723C>T (p.Pro908Leu)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323314	NM_032387.5(WNK4):c.679G>T (p.Gly227Trp)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323315	NM_032387.5(WNK4):c.717G>T (p.Ser239=)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323322	NM_032387.5(WNK4):c.1574G>A (p.Arg525His)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323332	NM_032387.5(WNK4):c.1885C>T (p.Arg629Cys)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323335	NM_032387.5(WNK4):c.2005C>T (p.Arg669Trp)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323341	NM_032387.5(WNK4):c.2588T>G (p.Leu863Arg)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3333179	NM_032387.5(WNK4):c.2212C>T (p.Arg738Trp)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3470775	NM_032387.5(WNK4):c.623G>A (p.Arg208Gln)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
64595	NM_032387.5(WNK4):c.1323A>T (p.Glu441Asp)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
760222	NM_032387.5(WNK4):c.2157+6G>C	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7663	NM_032387.5(WNK4):c.3553C>T (p.Arg1185Cys)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
889335	NM_032387.5(WNK4):c.1414C>G (p.Gln472Glu)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
889959	NM_032387.5(WNK4):c.246C>A (p.Asp82Glu)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890019	NM_032387.5(WNK4):c.1743G>A (p.Ser581=)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890655	NM_032387.5(WNK4):c.3032C>T (p.Pro1011Leu)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891515	NM_032387.5(WNK4):c.383C>G (p.Pro128Arg)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891519	NM_032387.5(WNK4):c.716C>G (p.Ser239Trp)	WNK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
WNK4	Strong	Autosomal dominant	pseudohypoaldosteronism type 2B	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNK4	Orphanet:88939	Pseudohypoaldosteronism type 2B

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
WNK4	HGNC:14544	ENSG00000126562	Q96J92	Serine/threonine-protein kinase WNK4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNK4	Serine/threonine-protein kinase WNK4	Serine/threonine-protein kinase component of the WNK4-SPAK/OSR1 kinase cascade, which acts as a key regulator of ion transport in the distal nephron and blood pressure.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WNK4	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
kidney epithelium	1
lower esophagus mucosa	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNK4	177	broad	marker	kidney epithelium, renal medulla, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WNK4	866

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WNK4	Q96J92	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Stimuli-sensing channels	1	135.9×	0.007	WNK4

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
aldosterone secretion	1	16852.0×	0.001	WNK4
distal tubule morphogenesis	1	8426.0×	0.001	WNK4
regulation of potassium ion export across plasma membrane	1	5617.3×	0.001	WNK4
renal sodium ion transport	1	4213.0×	0.001	WNK4
negative regulation of pancreatic juice secretion	1	3370.4×	0.001	WNK4
negative regulation of sodium ion transport	1	2808.7×	0.001	WNK4
monoatomic ion homeostasis	1	2407.4×	0.001	WNK4
intracellular chloride ion homeostasis	1	1685.2×	0.002	WNK4
response to dietary excess	1	1123.5×	0.002	WNK4
renal sodium ion absorption	1	991.3×	0.003	WNK4
macrophage activation	1	702.2×	0.003	WNK4
negative regulation of protein localization to plasma membrane	1	624.1×	0.003	WNK4
chloride transport	1	455.5×	0.004	WNK4
calcium ion homeostasis	1	443.5×	0.004	WNK4
ERK1 and ERK2 cascade	1	318.0×	0.005	WNK4
cellular response to xenobiotic stimulus	1	240.7×	0.006	WNK4
regulation of blood pressure	1	221.7×	0.007	WNK4
sodium ion transmembrane transport	1	203.0×	0.007	WNK4
potassium ion transmembrane transport	1	135.9×	0.010	WNK4
intracellular protein localization	1	104.7×	0.012	WNK4
gene expression	1	79.9×	0.015	WNK4
protein phosphorylation	1	68.0×	0.017	WNK4
intracellular signal transduction	1	38.1×	0.028	WNK4
inflammatory response	1	37.7×	0.028	WNK4
signal transduction	1	16.1×	0.062	WNK4

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
WNK4	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
WNK4	63	Binding:63

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	1	WNK4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
WNK4	63	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.