WNK1

Chr 12

WNK lysine deficient protein kinase 1

Also known as: HSAN2, HSN2, KDP, PPP1R167, PRKWNK1, PSK, p65

NCBI Gene: 65125ENSG00000060237UniProt: Q9H4A3

This gene encodes a member of the WNK subfamily of serine/threonine protein kinases. The encoded protein may be a key regulator of blood pressure by controlling the transport of sodium and chloride ions. Mutations in this gene have been associated with pseudohypoaldosteronism type II and hereditary sensory neuropathy type II. Alternatively spliced transcript variants encoding different isoforms have been described but the full-length nature of all of them has yet to be determined.[provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

UniProtPseudohypoaldosteronism 2C
UniProtNeuropathy, hereditary sensory and autonomic, 2A
477
ClinVar variants
19
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— WNK1
🧬
Gene-Disease Validity (ClinGen)
neuropathy, hereditary sensory and autonomic, type 2A · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 270 VUS of 477 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.13LOEUF
pLI 1.000
Z-score 8.82
OE 0.07 (0.04–0.13)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.16Z-score
OE missense 0.83 (0.79–0.87)
1043 obs / 1258.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.07 (0.04–0.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.79–0.87)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 7 / 104.2Missense obs/exp: 1043 / 1258.9Syn Z: -0.88

ClinVar Variant Classifications

477 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic8
VUS270
Likely Benign185
Benign1
Conflicting2
11
Pathogenic
8
Likely Pathogenic
270
VUS
185
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
5
0
11
Likely Pathogenic
5
1
2
0
8
VUS
5
248
13
4
270
Likely Benign
1
2
38
144
185
Benign
0
0
1
0
1
Conflicting
—2
Total1725159148477

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

WNK1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

WNK1-related neuropathy, hereditary sensory and autonomic

definitive
ARLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — WNK1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Familial Hyperkalemic Hypertension.
Cornelius RJ et al.·Compr Physiol
2024Review
WNK1 in the kidney.
Bahena-Lopez JP et al.·Curr Opin Nephrol Hypertens
2022Review
L-Wnk1 Deletion in Smooth Muscle Cells Causes Aortitis and Inflammatory Shift.
Quelquejay H et al.·Circ Res
2024
The Molecular Genetics of Gordon Syndrome.
Mabillard H et al.·Genes (Basel)
2019Review
Impact of periodontitis on type 2 diabetes: a bioinformatic analysis.
Wei X et al.·BMC Oral Health
2024
Chloride deregulation and GABA depolarization in MTOR-related malformations of cortical development.
Bakouh N et al.·Brain
2025
Phase II trial of imatinib mesylate in patients with PDGFRA/B-negative hypereosinophilic syndrome.
Kim DH et al.·Br J Haematol
2024Clinical trial
SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure.
Li H et al.·PLoS Pathog
2024
WNK1/HSN2 mediates neurite outgrowth and differentiation via a OSR1/GSK3β-LHX8 pathway.
Shimizu M et al.·Sci Rep
2022
Genetic predisposition to bevacizumab-induced hypertension.
Frey MK et al.·Gynecol Oncol
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools