WNK4

protein-coding

WNK lysine deficient protein kinase 4, the group of WNK lysine deficient protein kinases

Gene summary

This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]

Previous symbols:

PRKWNK4

MANE transcript

NM_032387.5

Inheritance

ClinVar variants

P:6U:423B:166

Top phenotype

Pseudohypoaldosteronism, type IIB

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr17:42,780,610-42,797,066

External References & Databases

Ensembl (ENSG00000126562)

Transcript & Mutation Effects

hg38 • Region Span ~16.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pseudohypoaldosteronism type 2BMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013777

Submitter: Ambry Genetics

pseudohypoaldosteronism type 2BSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013777

Submitter: Labcorp Genetics (formerly Invitae)

pseudohypoaldosteronism type 2BSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013777

Submitter: PanelApp Australia

pseudohypoaldosteronism type 2BDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013777

Submitter: ClinGen

*WNK4* was first reported in relation to autosomal dominant pseudohypoaldosteronism (PHAII) in 2001 (Wilson et al., PMID: 11498583). Features of affected probands are hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis. 12 variants (all missense) that have been reported in at least 13 probands in 10 publications (PMIDs: 11498583, 15292344, 15998707, 19016006, 21196779, 21764813, 26920127, 30773290, 31044551, 34622103) are included in this curation. Mutations causative of disease cluster in exons 7 and 17. The genetic mechanism of pathogenicity appears to be gain-of-function (PMID: 11498583). This results in gain of NCC (NaCl cotransporter) function through loss of degradation (PMID: 12515852) and loss of inhibitory regulation of ROMK (renal outer medullary potassium channel). Features caused by WNK4 variants in PHAII are the reverse phenotype of those caused by loss-of-function variants in NCC associated with Gitelman Syndrome. This gene-disease relationship is also supported by experimental evidence (mouse models, interaction evidence, expression-level evidence; PMIDs: 16964266, 17488636, 33491560). Mouse models expressing disease-causing WNK4 variants recapitulate the human phenotype of hypertension, hyperkalemia, and hypercalciuria. Mouse models also show that OSR1/SPAK kinase-NCC phosphorylation is activated by mutated WNK4, leading to disease. WNK4 is strongly expressed in the human kidney, based on Northern blot and Humphrey's lab data. WNK4 protein concentrations are controlled by the function of the cullin 3 (CUL3)-Kelch-like family member 3 (KLHL3) E3 ligase complex. CUL3 and KLHL3 are both definitively associated with pseudohypoaldosteronism. In summary, there is definitive evidence supporting the relationship between WNK4 and autosomal dominant pseudohypoaldosteronism. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 7/21/2026 (SOP Version 12).

Clinical Genomic Database (CGD)

Pseudohypoaldosteronism, type IIBAD

Manifestation: Renal

Intervention: Renal

Rationale: Treatment (eg, correction of physiologic abnormalities by thiazide diuretics) can be effective, and measures towards optimizing blood pressure can decrease morbidity and mortality related to potential sequale of hypertension

Refs: 718349; 718348; 504550; 6103235; 9171836; 11498583; 19016006; 22266938; 22073419

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WNK4 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 331

Pseudohypoaldosteronism type 2BTotal: 276

Inborn genetic diseasesTotal: 196

not specifiedTotal: 56

WNK4-related disorderTotal: 23

Renal tubulopathiesTotal: 1

Connective tissue disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032387.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			17 clinvar	74 clinvar	14 clinvar	105
missense	3 clinvar	2 clinvar	363 clinvar	66 clinvar	9 clinvar	443
nonsense			12 clinvar	1 clinvar		13
start loss						0
frameshift		1 clinvar	25 clinvar	1 clinvar		27
splice donor/acceptor (+/-2bp)			6 clinvar	1 clinvar		7
Total	3	3	423	143	23	595

Highest pathogenic variant AF is 0.0000020521463

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032387.5	RefSeq	NP_115763.2	19	MANE Select
ENST00000246914.10	Ensembl	ENSP00000246914.4	19	MANE Select
NM_001321299.2	RefSeq	NP_001308228.1	16	Standard
ENST00000587745.1	Ensembl	ENSP00000467312.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Diuretics Pathway, Pharmacodynamics
Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

protein phosphorylation
ion transport
chloride transport
protein localization
negative regulation of sodium ion transport

Molecular Function

protein serine/threonine kinase activity
protein binding
ATP binding
chloride channel inhibitor activity
potassium channel inhibitor activity

Cellular Component

cytoplasm
cytosol
bicellular tight junction
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000246914
Coding exons: 18
Length: 16259
Individuals with no LoFs: 125485
Homozygous LoFs: 0
Heterozygous LoFs: 263
Defined: 125748
p: 0.00105

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.814	665	727	0.915	0.0000451	7898
Missense (PolyPhen)		104	99.883	1.0412		1073
Synonymous	0.690	292	307	0.950	0.0000195	2739
Loss of Function	1.26	43	52.9	0.813	0.00000303	570

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.00081	0.00081	rare
Ashkenazi Jewish	0.00021	0.00020	rare
East Asian	0.0025	0.0024	notable
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.0013	0.0013	notable
South Asian	0.00065	0.00065	rare
Other	0.00099	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SCNN1A, SCNN1B, SCNN1D, SGK1, TRPV5 and TRPV6. Regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation which appears to prevent membrane trafficking of SLC12A3. Also inhibits the renal K(+) channel, KCNJ1, via a kinase-independent mechanism by which it induces clearance of the protein from the cell surface by clathrin-dependent endocytosis. WNK4 appears to act as a molecular switch that can vary the balance between NaCl reabsorption and K(+) secretion to maintain integrated homeostasis. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity). {ECO:0000250|UniProtKB:Q80UE6, ECO:0000269|PubMed:20525693}.;
Disease: DISEASE: Pseudohypoaldosteronism 2B (PHA2B) [MIM:614491]: An autosomal dominant disorder characterized by hypertension, hyperkalemia, hyperchloremia, mild hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. {ECO:0000269|PubMed:11498583, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.246

Intolerance Scores

LoFtool: 0.889
RVIS EVS: 0.37
RVIS percentile EVS: 74.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.814

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium