WNK3

Chr XXLR

WNK lysine deficient protein kinase 3

Also known as: MRXS2, PRKWNK3, PRS

NCBI Gene: 65267ENSG00000196632UniProt: Q9BYP7

This gene encodes a protein belonging to the 'with no lysine' family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase-3-dependent pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

Prieto syndromeMIM #309610
XLR
514
ClinVar variants
33
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— WNK3
⚡
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
33 Pathogenic / Likely Pathogenic· 197 VUS of 514 total submissions

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.
0.19LOEUF
pLI 1.000
Z-score 6.26
OE 0.09 (0.05–0.19)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
2.55Z-score
OE missense 0.71 (0.66–0.77)
453 obs / 633.8 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.0.09 (0.05–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.66–0.77)
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.0.86
0≤1.21.6
LoF obs/exp: 5 / 55.1Missense obs/exp: 453 / 633.8Syn Z: 1.68

ClinVar Variant Classifications

514 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic5
VUS197
Likely Benign29
Benign12
Conflicting8
28
Pathogenic
5
Likely Pathogenic
197
VUS
29
Likely Benign
12
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
3
23
0
28
Likely Pathogenic
1
0
4
0
5
VUS
3
180
13
1
197
Likely Benign
0
21
2
6
29
Benign
0
2
5
5
12
Conflicting
—8
Total62064712279

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

View in ClinVar →

Protein Context — Lollipop Plot

WNK3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

WNK3-related neurodevelopmental disorder

moderate
Monoallelic X HemizygousUndeterminedAbsent Gene Product, Altered Gene Product Structure
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Prieto syndrome

MIM #309610

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole exome sequencing analysis of 167 men with primary infertility.
Zhou H et al.·BMC Med Genomics
2024
Rare pathogenic variants in WNK3 cause X-linked intellectual disability.
Küry S et al.·Genet Med
2022
Influence of WNK3 on intracellular chloride concentration and volume regulation in HEK293 cells.
Cruz-Rangel S et al.·Pflugers Arch
2012
Similar effects of all WNK3 variants on SLC12 cotransporters.
Cruz-Rangel S et al.·Am J Physiol Cell Physiol
2011
WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function.
Yoon HJ et al.·Exp Mol Med
2022
Autism-associated familial microdeletion of Xp11.22.
Qiao Y et al.·Clin Genet
2008Case report
Point-of-care whole-exome sequencing of idiopathic male infertility.
Fakhro KA et al.·Genet Med
2018
Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.
Zhou X et al.·Cancer Sci
2019Cohort
Genotype-phenotype correlation in Gordon's syndrome: report of two cases carrying novel heterozygous mutations.
Anglani F et al.·J Nephrol
2022Case report
WNK kinases, a novel protein kinase subfamily in multi-cellular organisms.
Veríssimo F et al.·Oncogene
2001
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