pseudohypoaldosteronism type 2C

Summary

pseudohypoaldosteronism type 2C (MONDO:0013778) is a disease caused by WNK1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: WNK1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 2,089

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoaldosteronism type 2C
Mondo ID	MONDO:0013778
MeSH	C564162
OMIM	614492
Orphanet	88940
ICD-11	1052840113
UMLS	C1840391
MedGen	327089
GARD	0016777
Is cancer (heuristic)	no

Also known as: PHA2C · pseudohypoaldosteronism type 2 caused by mutation in WNK1 · pseudohypoaldosteronism, type IIC · WNK1 pseudohypoaldosteronism type 2

Data availability: 2,089 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 2C

Related subtypes (4): pseudohypoaldosteronism type 2A, pseudohypoaldosteronism type 2B, 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

600 retrieved; paginated sample, class counts are floors:

328 uncertain significance, 224 likely benign, 21 conflicting classifications of pathogenicity, 10 benign/likely benign, 9 benign, 7 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069964	NM_213655.5(WNK1):c.2436C>A (p.Tyr812Ter)	WNK1	Pathogenic	criteria provided, single submitter
1071299	NM_213655.5(WNK1):c.2462_2463dup (p.Ile822fs)	WNK1	Pathogenic	criteria provided, single submitter
1075747	NM_213655.5(WNK1):c.3088_3091del (p.Val1030fs)	WNK1	Pathogenic	criteria provided, single submitter
1393975	NM_213655.5(WNK1):c.3373C>T (p.Gln1125Ter)	WNK1	Pathogenic	criteria provided, single submitter
1452033	NM_213655.5(WNK1):c.3096del (p.Pro1033fs)	WNK1	Pathogenic	criteria provided, single submitter
1452138	NM_213655.5(WNK1):c.3535C>T (p.Gln1179Ter)	WNK1	Pathogenic	criteria provided, single submitter
1998479	NM_213655.5(WNK1):c.2446_2449del (p.Gln816fs)	WNK1	Pathogenic	criteria provided, single submitter
1525795	NM_018979.4(WNK1):c.6448+2T>C	WNK1	Likely pathogenic	criteria provided, single submitter
1011873	NM_018979.4(WNK1):c.4788A>G (p.Gln1596=)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1039744	NM_213655.5(WNK1):c.2219dup (p.Phe741fs)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041731	NM_018979.4(WNK1):c.5086G>A (p.Ala1696Thr)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1057218	NM_018979.4(WNK1):c.5325C>T (p.Ser1775=)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060396	NM_213655.5(WNK1):c.2228_2229dup (p.Thr744fs)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1077890	NM_018979.4(WNK1):c.3292A>G (p.Thr1098Ala)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1081822	NM_018979.4(WNK1):c.397G>A (p.Val133Ile)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1084421	NM_018979.4(WNK1):c.6958A>G (p.Met2320Val)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1094977	NM_213655.5(WNK1):c.2201C>T (p.Pro734Leu)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1095959	NM_018979.4(WNK1):c.5584-5A>G	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1362976	NM_018979.4(WNK1):c.2119G>A (p.Val707Ile)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1393159	NM_213655.5(WNK1):c.2464A>G (p.Ile822Val)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1472148	NM_213655.5(WNK1):c.2233G>A (p.Ala745Thr)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1525821	NM_018979.4(WNK1):c.5463G>A (p.Ala1821=)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1656182	NM_018979.4(WNK1):c.4130T>A (p.Val1377Glu)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1752186	NM_018979.4(WNK1):c.5448+1G>T	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1752403	NM_018979.4(WNK1):c.5491A>G (p.Thr1831Ala)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191028	NM_213655.5(WNK1):c.2152C>T (p.Arg718Cys)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194667	NM_018979.4(WNK1):c.3578G>A (p.Ser1193Asn)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195834	NM_018979.4(WNK1):c.5734A>C (p.Ile1912Leu)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195979	NM_018979.4(WNK1):c.6624C>A (p.Ser2208Arg)	WNK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000257	NM_018979.4(WNK1):c.1933C>T (p.Pro645Ser)	WNK1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
WNK1	Strong	Autosomal dominant	pseudohypoaldosteronism type 2C	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNK1	Orphanet:88940	Pseudohypoaldosteronism type 2C
WNK1	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2

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
WNK1	HGNC:14540	ENSG00000060237	Q9H4A3	Serine/threonine-protein kinase WNK1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNK1	Serine/threonine-protein kinase WNK1	Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx.

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)
WNK1	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
globus pallidus	1
inferior vagus X ganglion	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNK1	297	ubiquitous	marker	medial globus pallidus, globus pallidus, inferior vagus X ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WNK1	371

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WNK1	Q9H4A3	5

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	WNK1

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
positive regulation of termination of RNA polymerase II transcription	1	16852.0×	0.002	WNK1
negative regulation of cell-cell adhesion mediated by integrin	1	8426.0×	0.002	WNK1
monoatomic cation homeostasis	1	8426.0×	0.002	WNK1
chemokine (C-C motif) ligand 21 signaling pathway	1	4213.0×	0.002	WNK1
lymphocyte migration into lymph node	1	4213.0×	0.002	WNK1
negative regulation of pancreatic juice secretion	1	3370.4×	0.002	WNK1
negative regulation of sodium ion transport	1	2808.7×	0.002	WNK1
negative regulation of leukocyte cell-cell adhesion	1	2808.7×	0.002	WNK1
positive regulation of mitotic cytokinesis	1	2808.7×	0.002	WNK1
regulation of mRNA export from nucleus	1	2106.5×	0.002	WNK1
regulation of monoatomic cation transmembrane transport	1	2106.5×	0.002	WNK1
negative regulation of heterotypic cell-cell adhesion	1	1872.4×	0.002	WNK1
intracellular chloride ion homeostasis	1	1685.2×	0.002	WNK1
protein insertion into ER membrane by stop-transfer membrane-anchor sequence	1	1532.0×	0.002	WNK1
positive regulation of systemic arterial blood pressure	1	1404.3×	0.002	WNK1
negative regulation of small GTPase mediated signal transduction	1	1203.7×	0.002	WNK1
cellular hyperosmotic response	1	1203.7×	0.002	WNK1
positive regulation of T cell chemotaxis	1	1123.5×	0.002	WNK1
membraneless organelle assembly	1	1123.5×	0.002	WNK1
regulation of sodium ion transmembrane transport	1	1053.2×	0.002	WNK1
cellular response to chemokine	1	991.3×	0.002	WNK1
regulation of sodium ion transport	1	936.2×	0.002	WNK1
potassium ion homeostasis	1	766.0×	0.002	WNK1
negative regulation of protein localization to plasma membrane	1	624.1×	0.003	WNK1
cell volume homeostasis	1	601.9×	0.003	WNK1
negative regulation of protein ubiquitination	1	285.6×	0.005	WNK1
negative regulation of autophagy	1	259.3×	0.005	WNK1
neuron development	1	255.3×	0.005	WNK1
sodium ion transmembrane transport	1	203.0×	0.006	WNK1
monoatomic ion transport	1	156.0×	0.008	WNK1

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
WNK1	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
WNK1	165	Binding:165

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
WNK1	165

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	WNK1
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)
WNK1	165	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.