WNK3

Chr XXLR

WNK lysine deficient protein kinase 3

Also known as: MRXS2, PRKWNK3, PRS

WNK3 encodes a serine/threonine protein kinase that regulates electrolyte homeostasis by phosphorylating and activating downstream kinases that control ion cotransporter activity, and also enhances calcium transport through TRPV5 and TRPV6 channels. Mutations cause Prieto syndrome, an X-linked recessive disorder. The gene is highly constrained against loss-of-function variants, indicating intolerance to haploinsufficiency.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismXLRLOEUF 0.191 OMIM phenotype
Clinical SummaryWNK3
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
26 unique Pathogenic / Likely Pathogenic· 147 VUS of 319 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.19LOEUF
pLI 1.000
Z-score 6.26
OE 0.09 (0.050.19)
Highly constrained

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

Missense Constraint
2.55Z-score
OE missense 0.71 (0.660.77)
453 obs / 633.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.09 (0.050.19)
00.351.4
Missense OE0.71 (0.660.77)
00.61.4
Synonymous OE0.86
01.21.6
LoF obs/exp: 5 / 55.1Missense obs/exp: 453 / 633.8Syn Z: 1.68
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
moderateWNK3-related neurodevelopmental disorderOTHERXLR
DN
0.2698th %ile
GOF
0.3491th %ile
LOF
0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.19

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

319 submitted variants in ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic1
VUS147
Likely Benign19
Conflicting6
25
Pathogenic
1
Likely Pathogenic
147
VUS
19
Likely Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
23
0
25
Likely Pathogenic
1
0
0
0
1
VUS
3
137
6
1
147
Likely Benign
0
16
1
2
19
Benign
0
0
0
0
0
Conflicting
6
Total6153303198

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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