WNK4

Chr 17q21.2

WNK lysine deficient protein kinase 4

MANE:: ENST00000246914.10

OMIM: 601844 ↗NCBI: 65266 ↗Ensembl ↗

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Predicted protein structure

AlphaFold predicted structure

WNK4 · Q96J92

v62025-08-01

Predicted Aligned Error matrix for WNK4 — diagonal shows residue index, colour shows pairwise prediction confidence (lower is better) — Predicted Aligned Error

Mean pLDDT

57.0/ 100

Low

1,243 residues

Confidence breakdown

Very high(≥ 90)18%
Confident(70–90)18%
Low(50–70)7%
Very low(< 50)56%

Open interactive 3D viewer

AlphaFold (Jumper et al., 2021) · CC BY 4.0

Clinical relevance (Genomics England PanelApp)

Diagnostic Grade (Green)

Extreme early-onset hypertension
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Renal tubulopathies
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Disease associations (Open Targets)

pseudohypoaldosteronism type 2B
0.75
pseudohypoaldosteronism type 2
0.38
neurodegenerative disease
0.37
knee fracture
0.23
hereditary disease
0.19
connective tissue disorder
0.12
hypertensive disorder
0.09
Hypertension
0.09
acute respiratory distress syndrome
0.08
familial idiopathic steroid-resistant nephrotic syndrome
0.08

Score is the Open Targets composite evidence score (0-1). Higher = stronger gene-disease association.

Protein function (UniProt)

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 (By similarity). The WNK4-SPAK/OSR1 kinase cascade is composed of WNK4, which mediates phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK (PubMed:16832045). Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters, such as SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A5/KCC2 or SLC12A6/KCC3, regulating their activity (PubMed:16832045, PubMed:22989884). Acts as a molecular switch that regulates the balance between renal salt reabsorption and K(+) secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter SLC12A3/NCC and the K(+) channel, KCNJ1/ROMK (By similarity). Regulates NaCl reabsorption in the distal nephron by activating the thiazide-sensitive Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney: activates SLC12A3/NCC in a OXSR1/OSR1- and STK39/SPAK-dependent process (By similarity). Also acts as a scaffold protein independently of its protein kinase activity: negatively regulates cell membrane localization of various transporters and channels (CFTR, KCNJ1/ROMK, SLC4A4, SLC26A9 and TRPV4) by clathrin-dependent endocytosis (By similarity). Also inhibits the activity of the epithelial Na(+) channel (ENaC) SCNN1A, SCNN1B, SCNN1D in a inase-independent mechanism (By similarity). May also phosphorylate NEDD4L (PubMed:20525693)