WNK2

Summary

WNK2 (WNK lysine deficient protein kinase 2, HGNC:14542) is a protein-coding gene on chromosome 9q22.31, encoding Serine/threonine-protein kinase WNK2 (Q9Y3S1). Serine/threonine-protein kinase component of the WNK2-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation.

The protein encoded by this gene is a cytoplasmic serine-threonine kinase that belongs to the protein kinase superfamily. The protein plays an important role in the regulation of electrolyte homeostasis, cell signaling survival, and proliferation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 65268 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 3,151 total — 1 likely-pathogenic
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types
• MANE Select transcript: NM_006648

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14542
Approved symbol	WNK2
Name	WNK lysine deficient protein kinase 2
Location	9q22.31
Locus type	gene with protein product
Status	Approved
Aliases	NY-CO-43, KIAA1760
Ensembl gene	ENSG00000165238
Ensembl biotype	protein_coding
OMIM	606249
Entrez	65268

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 12 protein_coding, 6 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000297954, ENST00000395477, ENST00000411624, ENST00000427277, ENST00000432730, ENST00000448039, ENST00000453718, ENST00000460335, ENST00000462595, ENST00000464625, ENST00000467401, ENST00000471076, ENST00000478583, ENST00000479696, ENST00000693671, ENST00000913009, ENST00000913010, ENST00000913011, ENST00000913012, ENST00000913013

RefSeq mRNA: 2 — MANE Select: NM_006648 NM_001282394, NM_006648

CCDS: CCDS75858

Canonical transcript exons

ENST00000427277 — 30 exons

Exon	Start	End
ENSE00003470660	93306777	93306821
ENSE00003493905	93292491	93293173
ENSE00003514967	93229696	93229868
ENSE00003515238	93263566	93263734
ENSE00003523499	93268020	93268065
ENSE00003523817	93234808	93234965
ENSE00003536955	93238233	93238321
ENSE00003545658	93288788	93289620
ENSE00003547416	93256948	93257139
ENSE00003575167	93300051	93300149
ENSE00003579582	93261814	93262107
ENSE00003584089	93247543	93247834
ENSE00003585991	93267746	93267916
ENSE00003586453	93256299	93256454
ENSE00003590340	93263917	93264033
ENSE00003593679	93262670	93262719
ENSE00003610646	93268627	93268746
ENSE00003619254	93317520	93317631
ENSE00003641349	93252883	93253082
ENSE00003644359	93230888	93231108
ENSE00003647374	93184928	93185610
ENSE00003662082	93299070	93299261
ENSE00003670972	93297853	93298067
ENSE00003690555	93292308	93292396
ENSE00003692836	93239757	93239976
ENSE00003729308	93258931	93259614
ENSE00003740111	93289978	93290047
ENSE00003787333	93308328	93308584
ENSE00003929307	93320367	93320569
ENSE00003936757	93184139	93184385

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 97.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0330 / max 12.6286, expressed in 12 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
97404	0.0136	8
97407	0.0124	4
97406	0.0070	4

Top tissues by expression

251 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.91	gold quality
right uterine tube	UBERON:0001302	97.44	gold quality
right atrium auricular region	UBERON:0006631	97.35	gold quality
cardiac atrium	UBERON:0002081	96.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.68	gold quality
body of pancreas	UBERON:0001150	96.41	gold quality
cerebellar hemisphere	UBERON:0002245	96.12	gold quality
cerebellar cortex	UBERON:0002129	96.01	gold quality
transverse colon	UBERON:0001157	95.73	gold quality
adenohypophysis	UBERON:0002196	95.70	gold quality
ganglionic eminence	UBERON:0004023	95.64	gold quality
cortical plate	UBERON:0005343	95.25	gold quality
heart left ventricle	UBERON:0002084	95.24	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.11	gold quality
mucosa of transverse colon	UBERON:0004991	94.94	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.92	gold quality
cardiac ventricle	UBERON:0002082	94.81	gold quality
left ventricle myocardium	UBERON:0006566	94.81	silver quality
cerebellum	UBERON:0002037	94.79	gold quality
right frontal lobe	UBERON:0002810	94.59	gold quality
pituitary gland	UBERON:0000007	94.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.79	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.56	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.07	gold quality
lower esophagus	UBERON:0013473	93.02	gold quality
gastrocnemius	UBERON:0001388	92.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.70	gold quality
mucosa of stomach	UBERON:0001199	92.43	gold quality
parotid gland	UBERON:0001831	92.29	gold quality
anterior cingulate cortex	UBERON:0009835	92.17	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.40
E-MTAB-5061	no	3.38
E-GEOD-137537	no	3.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53, ZNF160

miRNA regulators (miRDB)

7 targeting WNK2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-3611	98.76	68.76	1290
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-3654	96.43	66.55	646

Literature-anchored findings (GeneRIF, showing 20)

• epigenetic silencing, occasional deletion and point mutation, and functional assessment suggest that aberrations of WNK2 may contribute to unregulated tumor cell growth (PMID:17578925)
• WNK2 is involved in the modulation of growth factor-induced cancer cell proliferation through the MEK1/ERK1/2 pathway. (PMID:17667937)
• WNK2 controls a RhoA-mediated cross-talk mechanism that regulates the efficiency with which MEK1 can activate ERK1/2 upon growth factor stimulation. (PMID:18593598)
• Epigenetic silencing of the kinase tumor suppressor WNK2 is tumor-type and tumor-grade specific. (PMID:19001526)
• a role for WNK2 in the regulation of CCCs in the mammalian brain, with implications for both cell volume regulation and/or GABAergic signaling. (PMID:21733846)
• results validate the WNK2 gene as a recurrent target for epigenetic silencing in glia-derived brain tumours and provide first mechanistic evidence for a tumour-suppressing role of WNK2 that is related to Rac1 signalling and tumour cell invasion and growth (PMID:23035050)
• Wnk kinases are positive regulators of canonical Wnt/beta-catenin signaling. (PMID:23797875)
• Downregulation of WNK2 by promoter hypermethylation occurs early in Pancreatic ductal adenocarcinoma pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. (PMID:23912455)
• WNK2 promoter methylation and silencing in gliomas is associated with increased JNK activation and MMP2 expression and activity, thus explaining in part tumor cell invasion potential. (PMID:25596741)
• The data suggest that miR-370 acts as an oncogene by downregulating WNK2 in breast cancer. (PMID:31009242)
• Genomic sequencing identifies WNK2 as a driver in hepatocellular carcinoma and a risk factor for early recurrence. (PMID:31349001)
• Long non-coding RNA LINC00858 exerts a tumor-promoting role in colon cancer via HNF4alpha and WNK2 regulation. (PMID:31884577)
• WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line. (PMID:32093151)
• LINC00858 knockdown inhibits gastric cancer cell growth and induces apoptosis through reducing WNK2 promoter methylation. (PMID:32447640)
• Long non-coding RNA LINC00858 inhibits colon cancer cell apoptosis, autophagy, and senescence by activating WNK2 promoter methylation. (PMID:32768499)
• Circ_0001666 affects miR-620/WNK2 axis to inhibit breast cancer progression. (PMID:34061329)
• WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia. (PMID:35849656)
• Germline mutations in WNK2 could be associated with serrated polyposis syndrome. (PMID:36270769)
• Regional bias of tumor suppressor gene mutations of STARD8 and WNK2 in colon cancers. (PMID:38091885)
• PAX6-WNK2 Axis Governs Corneal Epithelial Homeostasis. (PMID:39453672)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	wnk2	ENSDARG00000104989
mus_musculus	Wnk2	ENSMUSG00000037989
rattus_norvegicus	Wnk2	ENSRNOG00000016684
drosophila_melanogaster	Wnk	FBGN0037098
caenorhabditis_elegans		WBGENE00006941

Paralogs (6): WNK1 (ENSG00000060237), NRBP1 (ENSG00000115216), WNK4 (ENSG00000126562), DSTYK (ENSG00000133059), NRBP2 (ENSG00000185189), WNK3 (ENSG00000196632)

Protein

Protein identifiers

Serine/threonine-protein kinase WNK2 — Q9Y3S1 (reviewed: Q9Y3S1)

Alternative names: Antigen NY-CO-43, Protein kinase lysine-deficient 2, Protein kinase with no lysine 2, Serologically defined colon cancer antigen 43

All UniProt accessions (6): A6PVV2, E9PCD1, Q9Y3S1, H0Y7J9, H0Y7R3, H0Y7T5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase component of the WNK2-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation. The WNK2-SPAK/OSR1 kinase cascade is composed of WNK2, which mediates phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK. Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters, regulating their activity. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SLC12A2, SCNN1A, SCNN1B, SCNN1D and SGK1 and inhibits SLC12A5. Negatively regulates the EGF-induced activation of the ERK/MAPK-pathway and the downstream cell cycle progression. Affects MAPK3/MAPK1 activity by modulating the activity of MAP2K1 and this modulation depends on phosphorylation of MAP2K1 by PAK1. WNK2 acts by interfering with the activity of PAK1 by controlling the balance of the activity of upstream regulators of PAK1 activity, RHOA and RAC1, which display reciprocal activity.

Subunit / interactions. Forms a complex with the phosphorylated form of STK39.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in various cancer cell lines (at protein level). Predominantly expressed in heart, brain, skeletal muscle and colon.

Post-translational modifications. Autophosphorylated. Autophosphorylation at Ser-352 and Ser-356 promotes its activity.

Activity regulation. Activation requires autophosphorylation of Ser-356 and, to a lower extent, Ser-352.

Miscellaneous. Incomplete sequence.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y3S1-1	1	yes
Q9Y3S1-2	2
Q9Y3S1-3	3
Q9Y3S1-4	4

RefSeq proteins (2): NP_001269323, NP_006639* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR024678	Kinase_OSR1/WNK_CCT	Domain
IPR050588	WNK_Ser-Thr_kinase	Family
IPR056865	CCTL2_WNK	Domain

Pfam: PF00069, PF12202, PF24889

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (76 total): compositionally biased region 20, modified residue 16, region of interest 15, splice variant 9, helix 4, binding site 3, strand 3, sequence variant 2, chain 1, domain 1, active site 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6ELM	X-RAY DIFFRACTION	1.14
6FBK	X-RAY DIFFRACTION	1.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3S1-F1	44.29	0.12

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 342 (proton acceptor)

Ligand- & substrate-binding residues (3): 205; 275–278; 325

Post-translational modifications (16): 19, 30, 45, 352, 356, 560, 1150, 1262, 1588, 1685, 1736, 1817, 1818, 1862, 1889, 2067

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 126 (showing top): GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, CAGCTG_AP4_Q5, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, CEBPB_01, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, MODULE_331, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION

GO Biological Process (11): protein phosphorylation (GO:0006468), DNA damage response (GO:0006974), negative regulation of cell population proliferation (GO:0008285), intracellular signal transduction (GO:0035556), protein autophosphorylation (GO:0046777), monoatomic ion homeostasis (GO:0050801), negative regulation of ERK1 and ERK2 cascade (GO:0070373), positive regulation of canonical Wnt signaling pathway (GO:0090263), positive regulation of sodium ion transmembrane transporter activity (GO:2000651), homeostatic process (GO:0042592), regulation of monoatomic cation transmembrane transport (GO:1904062)

GO Molecular Function (8): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
protein kinase activity	2
phosphorylation	1
protein modification process	1
cellular response to stress	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
signal transduction	1
protein phosphorylation	1
chemical homeostasis	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
sodium ion transmembrane transporter activity	1
positive regulation of ion transmembrane transporter activity	1
positive regulation of sodium ion transmembrane transport	1
regulation of sodium ion transmembrane transporter activity	1
biological_process	1
regulation of monoatomic ion transmembrane transport	1
monoatomic cation transmembrane transport	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

656 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WNK2	FGD3	Q5JSP0	761
WNK2	SLC12A3	P55017	693
WNK2	SLC12A2	P55011	670
WNK2	SLC12A5	Q9H2X9	640
WNK2	KCNJ1	P48048	610
WNK2	SLC12A4	Q9UP95	592
WNK2	SYT2	Q8N9I0	580
WNK2	FGD1	P98174	573
WNK2	SLC12A1	Q13621	567
WNK2	STK39	Q9UEW8	556
WNK2	MBP	P02686	542
WNK2	NEDD4L	Q96PU5	520
WNK2	SCNN1A	P37088	497
WNK2	ITSN1	Q15811	466
WNK2	SLC12A6	Q9UHW9	460

IntAct

26 interactions, top by confidence:

A	B	Type	Score
OPG044	DDX3X	psi-mi:“MI:0914”(association)	0.730
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
OXSR1	WNK2	psi-mi:“MI:0407”(direct interaction)	0.590
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
PKM	WNK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
WNK2	ABL1	psi-mi:“MI:0915”(physical association)	0.400
WNK2	FYN	psi-mi:“MI:0915”(physical association)	0.400
WNK2	SLC43A3	psi-mi:“MI:0915”(physical association)	0.400
WNK2	SMC1A	psi-mi:“MI:0915”(physical association)	0.400
WNK2	ESS2	psi-mi:“MI:0915”(physical association)	0.370
AAK1	PDHX	psi-mi:“MI:0914”(association)	0.350
WNK3	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
OXSR1	RBM25	psi-mi:“MI:0914”(association)	0.350
WNK1	XPO1	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
TSC22D4	PSMA7	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
TSC22D4	TBL1X	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
WNK2		psi-mi:“MI:0915”(physical association)	0.000
WNK2	WNK1	psi-mi:“MI:0915”(physical association)	0.000
WNK2	UBE2I	psi-mi:“MI:0915”(physical association)	0.000
ATXN1	WNK2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (45): WNK2 (Affinity Capture-MS), WNK2 (Affinity Capture-MS), WNK2 (Affinity Capture-MS), WNK2 (Affinity Capture-MS), WNK2 (Affinity Capture-RNA), WNK2 (Affinity Capture-RNA), WNK2 (Affinity Capture-MS), WNK2 (Affinity Capture-RNA), WNK2 (Protein-RNA), WNK2 (Proximity Label-MS), WNK2 (Proximity Label-MS), WNK2 (Affinity Capture-MS), WNK2 (Proximity Label-MS), WNK2 (Affinity Capture-MS), WNK2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I5ZN27, A4FU49, A6X8Z5, E1AZ71, F1N8V3, O35668, O54963, P0C7A2, P48165, P54256, P54257, P55917, P62025, Q01538, Q13127, Q14028, Q16799, Q28139, Q28181, Q2M1Z3, Q3SYS4, Q3UH66, Q5DW34, Q5IS59, Q5TCY1, Q62100, Q63803, Q63HN8, Q640N3, Q64548, Q6IR42, Q6PCN3, Q7Z2Y5, Q7Z6I6, Q811Q2, Q8C5W0, Q8CFC2, Q8K0T0, Q8NEP3, Q8VIG1

Diamond homologs: A0A078CGE6, A2AQW0, A2QHV0, A2YMV6, A9RVK2, A9SY39, C4YRB7, D4A280, M9PGC5, O14305, O24527, O75914, O81472, O88643, P0CY23, P0CY24, P35465, P41892, P83741, Q01577, Q03497, Q08E52, Q0CL79, Q0D541, Q0D598, Q0D847, Q13153, Q13177, Q17850, Q21029, Q29502, Q297L2, Q2QXC6, Q2QYL8, Q2RA93, Q2RBE3, Q2ULU3, Q2V338, Q2VWQ3, Q39008

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
WNK2	“up-regulates activity”	WNK1	phosphorylation
KLHL2	“down-regulates quantity by destabilization”	WNK2	binding
“Cullin 3-RBX1-Skp1”	“down-regulates quantity by destabilization”	WNK2	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Transcriptional and post-translational regulation of MITF-M expression and activity	5	35.7×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein phosphorylation	5	10.3×	7e-03
intracellular signal transduction	8	9.2×	5e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — HCC, LMS, PLMESO.

Clinical variants and AI predictions

ClinVar

3151 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	1881
Likely benign	1232
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
520975	NM_006648.4(WNK2):c.4801dup (p.Asp1601fs)	Likely pathogenic

SpliceAI

5714 predictions. Top by Δscore:

Variant	Effect	Δscore
9:93229693:TA:T	acceptor_loss	1.0000
9:93229694:A:AG	acceptor_gain	1.0000
9:93229694:AG:A	acceptor_gain	1.0000
9:93229695:G:A	acceptor_loss	1.0000
9:93229695:G:GG	acceptor_gain	1.0000
9:93229695:GG:G	acceptor_gain	1.0000
9:93229695:GGA:G	acceptor_gain	1.0000
9:93229695:GGACC:G	acceptor_gain	1.0000
9:93229857:G:T	donor_gain	1.0000
9:93229864:AAGAC:A	donor_gain	1.0000
9:93229865:AGAC:A	donor_gain	1.0000
9:93229866:GAC:G	donor_gain	1.0000
9:93229866:GACG:G	donor_gain	1.0000
9:93229866:GACGT:G	donor_loss	1.0000
9:93229867:AC:A	donor_gain	1.0000
9:93229867:ACG:A	donor_loss	1.0000
9:93229868:CGTAA:C	donor_loss	1.0000
9:93229869:G:C	donor_loss	1.0000
9:93229869:G:GG	donor_gain	1.0000
9:93234799:C:CA	acceptor_gain	1.0000
9:93234800:G:A	acceptor_gain	1.0000
9:93234803:CACA:C	acceptor_loss	1.0000
9:93234805:CAGG:C	acceptor_loss	1.0000
9:93234806:A:AG	acceptor_gain	1.0000
9:93234807:G:GG	acceptor_gain	1.0000
9:93234807:GGT:G	acceptor_gain	1.0000
9:93234962:CTGT:C	donor_gain	1.0000
9:93234964:GT:G	donor_gain	1.0000
9:93234965:TGTGA:T	donor_loss	1.0000
9:93234966:G:GA	donor_loss	1.0000

AlphaMissense

2328 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:93293164:T:C	L1937P	1.000
9:93297876:T:C	L1948P	1.000
9:93293155:T:C	L1934P	0.999
9:93297909:T:C	L1959P	0.999
9:93292707:T:C	F1785L	0.998
9:93292708:T:C	F1785S	0.998
9:93292709:C:A	F1785L	0.998
9:93292709:C:G	F1785L	0.998
9:93293167:G:C	R1938P	0.998
9:93297855:A:C	H1941P	0.998
9:93297911:T:G	Y1960D	0.998
9:93293109:A:C	S1919R	0.997
9:93293111:C:A	S1919R	0.997
9:93293111:C:G	S1919R	0.997
9:93297854:C:G	H1941D	0.997
9:93297921:T:C	L1963P	0.997
9:93293106:A:C	S1918R	0.996
9:93293108:C:A	S1918R	0.996
9:93293108:C:G	S1918R	0.996
9:93297858:T:C	L1942P	0.996
9:93297888:A:C	Q1952P	0.996
9:93297918:G:C	R1962P	0.995
9:93293113:A:T	D1920V	0.993
9:93297924:G:T	G1964V	0.992
9:93297928:G:C	K1965N	0.992
9:93297928:G:T	K1965N	0.992
9:93297905:G:C	A1958P	0.991
9:93292708:T:G	F1785C	0.989
9:93297855:A:G	H1941R	0.989
9:93297867:T:C	I1945T	0.989

dbSNP variants (sampled 300 via entrez): RS1000014740 (9:93198637 A>G), RS1000025099 (9:93204162 A>T), RS1000030805 (9:93282912 A>C), RS1000060335 (9:93187368 G>C), RS1000062971 (9:93279905 C>G), RS1000071977 (9:93240679 G>A), RS1000083666 (9:93249857 G>A), RS1000101269 (9:93293897 C>T), RS1000125374 (9:93214004 A>G,T), RS1000188812 (9:93245888 A>G), RS1000231126 (9:93310840 T>C), RS1000247484 (9:93203838 G>A,T), RS1000260047 (9:93273282 C>G,T), RS1000327093 (9:93230257 T>A), RS1000330983 (9:93215530 T>C)

Disease associations

OMIM: gene MIM:606249 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST006919_2	Ability to confide in someone	2.000000e-09
GCST006923_6	Loneliness	7.000000e-11
GCST006924_2	Loneliness (MTAG)	1.000000e-13
GCST008103_108	Bipolar disorder	4.000000e-06
GCST008760_13	Perceived sweetness of sucrose	8.000000e-06
GCST010703_187	Brain morphology (MOSTest)	6.000000e-11
GCST011983_15	Fasting glucose	1.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement
EFO:0007865	loneliness measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5639 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Wnk family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 25 [PMID: 17935989]	Inhibition	5.82	pKi

Binding affinities (BindingDB)

1 measured of 3 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3R,4R)-3-methoxy-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	3.93 nM	US-10189849: CDK inhibitors

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.03	IC50	934	nM	STAUROSPORINE
5.84	IC50	1450	nM	STAUROSPORINE
5.84	IC50	1460	nM	STAUROSPORINE
5.55	IC50	2785	nM	CHEMBL3702566
5.41	IC50	3892	nM	CHEMBL2171124
5.09	IC50	8086	nM	CHEMBL3683258
5.00	Kd	1e+04	nM	CHEMBL4848254

PubChem BioAssay actives

6 with measured affinity, of 495 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[2-[(4-chlorophenyl)methoxy]phenyl]-[5-[2-(methylamino)-1,3-thiazol-4-yl]-2,3-dihydroindol-1-yl]methanone	1802280: WNK In Vitro Radiometric Assays from Article 10.1021/acschembio.6b00511: “Discovery and Characterization of Allosteric WNK Kinase Inhibitors.”	ic50	0.0500	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	2198459: Inhibition of human WNK2 using myelin basic protein as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.9340	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone	701932: Inhibition of WNK2	ic50	3.8920	uM
N,N-dimethyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine	1752109: Binding affinity to wild-type human partial length WNK2 (V47 to D482 residues) expressed in mammalian expression system measured after 1 hr by competitive binding assay	kd	10.0000	uM

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression	2
sodium arsenite	decreases expression, increases expression	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Diethylhexyl Phthalate	decreases expression, increases abundance, increases methylation, increases expression	2
Estradiol	decreases expression, increases expression, affects cotreatment	2
Nickel	decreases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
pentanal	decreases expression	1
abrine	decreases expression	1
quinocetone	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Folic Acid	decreases expression	1
Gallic Acid	decreases expression	1
Lead	decreases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1

ChEMBL screening assays

178 unique, capped per target: 178 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1043843	Binding	Residual activity of WNK2 at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3LD	Abcam HEK293T WNK2 KO 1	Transformed cell line	Female
CVCL_B3LE	Abcam HEK293T WNK2 KO 2	Transformed cell line	Female
CVCL_TY09	HAP1 WNK2 (-) 1	Cancer cell line	Male
CVCL_TY10	HAP1 WNK2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.