WNT5A

Summary

WNT5A (Wnt family member 5A, HGNC:12784) is a protein-coding gene on chromosome 3p14.3, encoding Protein Wnt-5a (P41221). Ligand for members of the frizzled family of seven transmembrane receptors.

The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene encodes a member of the WNT family that signals through both the canonical and non-canonical WNT pathways. This protein is a ligand for the seven transmembrane receptor frizzled-5 and the tyrosine kinase orphan receptor 2. This protein plays an essential role in regulating developmental pathways during embryogenesis. This protein may also play a role in oncogenesis. Mutations in this gene are the cause of autosomal dominant Robinow syndrome. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 7474 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant Robinow syndrome 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 305 total — 3 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 116
• MANE Select transcript: NM_003392

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12784
Approved symbol	WNT5A
Name	Wnt family member 5A
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	hWNT5A
Ensembl gene	ENSG00000114251
Ensembl biotype	protein_coding
OMIM	164975
Entrez	7474

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000264634, ENST00000474267, ENST00000482079, ENST00000493406, ENST00000497027, ENST00000497817, ENST00000624674

RefSeq mRNA: 4 — MANE Select: NM_003392 NM_001256105, NM_001377271, NM_001377272, NM_003392

CCDS: CCDS46850, CCDS58835

Canonical transcript exons

ENST00000264634 — 5 exons

Exon	Start	End
ENSE00001032709	55479314	55479564
ENSE00001170531	55474337	55474629
ENSE00001533973	55486980	55487306
ENSE00001838984	55465715	55470550
ENSE00003544792	55480785	55480918

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.3026 / max 403.3573, expressed in 1136 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42566	3.2117	438
42567	2.6148	487
42574	2.0016	782
42568	1.1343	384
42561	0.8235	214
42580	0.4309	236
42573	0.4231	250
42572	0.3601	228
42575	0.2079	87
42563	0.2024	102

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.45	gold quality
parotid gland	UBERON:0001831	98.55	gold quality
decidua	UBERON:0002450	98.17	gold quality
oral cavity	UBERON:0000167	96.51	gold quality
germinal epithelium of ovary	UBERON:0001304	95.85	gold quality
gingiva	UBERON:0001828	95.64	gold quality
palpebral conjunctiva	UBERON:0001812	95.27	gold quality
gingival epithelium	UBERON:0001949	95.05	gold quality
esophagus squamous epithelium	UBERON:0006920	94.95	gold quality
urethra	UBERON:0000057	94.69	gold quality
squamous epithelium	UBERON:0006914	94.59	gold quality
endometrium	UBERON:0001295	94.50	gold quality
cervix squamous epithelium	UBERON:0006922	94.41	gold quality
epithelium of esophagus	UBERON:0001976	93.95	gold quality
periodontal ligament	UBERON:0008266	93.05	gold quality
mammalian vulva	UBERON:0000997	92.16	gold quality
pharyngeal mucosa	UBERON:0000355	91.95	gold quality
tongue squamous epithelium	UBERON:0006919	91.79	gold quality
cervix epithelium	UBERON:0004801	91.77	gold quality
penis	UBERON:0000989	89.61	gold quality
caput epididymis	UBERON:0004358	89.57	gold quality
epithelium of nasopharynx	UBERON:0001951	89.40	gold quality
eye	UBERON:0000970	89.28	gold quality
seminal vesicle	UBERON:0000998	88.99	gold quality
placenta	UBERON:0001987	88.69	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.67	gold quality
visceral pleura	UBERON:0002401	88.29	gold quality
uterus	UBERON:0000995	88.05	gold quality
tibia	UBERON:0000979	87.50	gold quality
mucosa of urinary bladder	UBERON:0001259	87.08	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	13220.35
E-MTAB-8559	yes	638.24
E-ANND-3	yes	13.19
E-MTAB-5061	yes	11.53
E-MTAB-9388	yes	9.73
E-ENAD-27	yes	7.34
E-GEOD-110499	no	635.77

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
MAP3K14	Activation
NFKBIA	Activation

Upstream regulators (CollecTRI, top): APP, CUX1, DLX5, ESR1, GLIS1, HOXB7, NFIA, NFIB, NFIX, NKX3-2, PAX2, PITX2, RELA, RORA, RUNX1, STAT3

miRNA regulators (miRDB)

160 targeting WNT5A, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548J-3P	99.94	72.61	4881

Literature-anchored findings (GeneRIF, showing 40)

• Frequent up-regulation of WNT5A mRNA in primary gastric cancer. (PMID:11956659)
• Increased expression of WNT5a is associated with cell motility and invasion of metastatic melanoma (PMID:12086864)
• WNT5a is upregulated by TNF-alpha in tumor cell lines (PMID:12165812)
• Wnt-5a promotes T cell nuclear accumulation of the transcription factor NFAT in the presence of cyclosporin A. (PMID:12244165)
• These results suggest that the TAK1-NLK MAPK cascade is activated by the noncanonical Wnt-5a/Ca(2+) pathway and antagonizes canonical Wnt/beta-catenin signaling. (PMID:12482967)
• Results suggest that disabled-2 functions as a negative regulator of canonical Wnt signaling by stabilizing the beta-catenin degradation complex. (PMID:12805222)
• Down-regulation of Wnt-4 and up-regulation of Wnt-5a are possible markers of the malignant phenotype of human squamous cell carcinoma. (PMID:12841867)
• Altered mRNA expression is associated with prostate cancer recurrence. (PMID:15067324)
• Their different spatial expression patterns suggest that Wnt4 and Wnt5a proteins are not functionally linked to type II collagen and type X collagen synthesis in in vitro chondrogenic models of mesenchyme stem cells (PMID:15389636)
• Wnt-5a is involved in the response of malignant neuroblasts to retinoic acid. (PMID:15592517)
• Wnt-5a serves as an antagonist to the canonical Wnt-signaling pathway with tumor suppressor activity in differentiated thyroid carcinomas. (PMID:15735754)
• Over-expression of Wnt5a in transgenic mice disrupts epithelial-response to FGF10 and regulates Shh signaling. (PMID:16169547)
• The role of Wnt5A in the microenvironment of primary breast cancer and macrophage-induced breast cancer invasion. (PMID:16569699)
• function of Wnt 5a as either a suppressor or promoter of malignant progression seems to be modulated by intercellular interactions (PMID:16569699)
• WNT5A and FZD5 regulate the microbially induced interleukin-12 response of antigen-presenting cells and interferon-gamma production by mycobacterial antigen-stimulated T cells (PMID:16601243)
• NFAT1, a transcription factor connected with breast cancer metastasis, is activated by Wnt-5a through a Ca2+ signaling pathway in human breast epithelial cells which was simultaneously counteracted by a Wnt-5a-induced Yes/Cdc42 signaling pathway. (PMID:16880514)
• The Embryonic Lethal Abnormal Vision-like protein HuR, inhibited translation of Wnt-5a when bound to highly conserved AU-rich sequences in the 3’-untranslated region of the Wnt-5a mRNA. (PMID:16914445)
• The aberrant expression of WNT5A suggest that the Wnt signaling pathway may be abnormally regulated in nasopharyngeal carcinoma (NPC), which provides insight into the molecular mechanisms of NPC. (PMID:16996564)
• Screening for Wnt5a-regulated genes in cultured endothelial cells identified several encoding angiogenic regulators, including matrix metalloproteinase-1, an interstitial collagenase, and Tie-2, a receptor for angiopoietins. (PMID:17035633)
• WNT5A is an important target of CUTL1 and mediator of invasiveness and tumor progression in pancreatic cancer. (PMID:17227781)
• Wnt5A can signal via protein kinase C (PKC), so the role of PKC in Wnt5A-mediated motility and epithelial to mesenchymal transition was also assessed using PKC inhibition and activation studies (PMID:17426020)
• Wnt3A/5A can function as mesenchymal regulatory factors by providing instructive cues for the recruitment, maintenance, and differentiation of mesenchymal stem cells. (PMID:17458904)
• Our findings demonstrate that APC status plays a key role as a determinant of Wnt5a secretion and suggest that CaSR-mediated secretion of Wnt5a will inhibit defective Wnt signaling in APC-truncated cells in an autocrine manner. (PMID:17463182)
• Hypomethylation of wingless-related MMTV integration site 5A (WNT5A), S100 calcium-binding protein P (S100P) and cysteine-rich protein 1(CRIP1) was confirmed in the cancer cells by bisulfite sequencing. (PMID:17486081)
• Ability of phenylmethimazole (C10) to decrease growth and migration of papillary thyroid cancer cells may be related to its suppressive effect on TLR3 and Wnt5a signaling. (PMID:17525119)
• These results suggest that Wnt signaling crosstalk and functional antagonism with the LRP5 co-receptor are key signaling regulators of mesenchymal stem cells maintenance and differentiation. (PMID:17546602)
• Data indicate that Wnt5a signaling is an important regulator in the proliferation of glioma cells. (PMID:17709179)
• did not detect submicroscopic deletion or duplication nor sequence alteration in either CACNA2D3 or WNT5A in ZLS-affected individuals (PMID:17937436)
• Review about the different influences and signaling pathways of Wnt5A in tumor progression. (PMID:17952396)
• The genesis of myelocytic leukemia is related to the down-regulated expression of Wnt5a. (PMID:17956663)
• Wnt5a and Wnt11 expression in EPC cells was induced by coculture with rat neonatal cardiomyocyte and was blocked by gamma-secretase inhibition. (PMID:17967789)
• Our findings suggest non-canonical Wnt signalling plays a role in regulating endothelial cell growth and possibly in angiogenesis. (PMID:17986384)
• These data show activation of the Wnt/beta-catenin-signalling pathway in uveal melanoma and suggest that components of this pathway might be useful prognostic markers as well as attractive therapeutic targets to treat this disease. (PMID:17992121)
• WNT5A, a putative tumour suppressor gene in ALL, is silenced by methylation in this disease and that this epigenetic event is associated with upregulation of CYCLIN D1 expression and confers poor prognosis in patients with ALL. (PMID:18032022)
• WNT5A is frequently inactivated in CRC by tumor-specific methylation, and thus, is a potential biomarker. (PMID:18172252)
• MT1-MMP-induced phenotypic changes were dependent upon up-regulation of Wnt5a, which has been implicated in epithelial-to-mesenchymal transition. (PMID:18174174)
• Wnt5A is critically involved in inflammatory macrophage signaling in sepsis and is a target for antiinflammatory mediators like APC or antagonists like sFRP1. (PMID:18174455)
• findings show cell-autonomous mechanisms allow Wnt5a to control cell orientation, polarity, and directional movement in response to positional cues from chemokine gradients (PMID:18420933)
• Wnt5a expressed in atherosclerotic lesions colocalizes with TLR-4. (PMID:18456733)
• study demonstrated that Wnt3a & Wnt5a can promote proliferation of HEK293 cells & inhibit serum starvation-induced apoptosis, which implies Wnt3a & Wnt5a can maintain survival of HEK293 cells under stress (PMID:18462958)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	wnt5a	ENSDARG00000104973
mus_musculus	Wnt5a	ENSMUSG00000021994
rattus_norvegicus	Wnt5a	ENSRNOG00000015618
drosophila_melanogaster	Wnt2	FBGN0004360
drosophila_melanogaster	Wnt5	FBGN0010194
drosophila_melanogaster	Wnt10	FBGN0031903
caenorhabditis_elegans		WBGENE00000857
caenorhabditis_elegans		WBGENE00000858
caenorhabditis_elegans	lin-44	WBGENE00003029

Paralogs (18): WNT16 (ENSG00000002745), WNT8A (ENSG00000061492), WNT8B (ENSG00000075290), WNT11 (ENSG00000085741), WNT2 (ENSG00000105989), WNT3 (ENSG00000108379), WNT5B (ENSG00000111186), WNT6 (ENSG00000115596), WNT1 (ENSG00000125084), WNT2B (ENSG00000134245), WNT10A (ENSG00000135925), WNT9A (ENSG00000143816), WNT3A (ENSG00000154342), WNT7A (ENSG00000154764), WNT9B (ENSG00000158955), WNT4 (ENSG00000162552), WNT10B (ENSG00000169884), WNT7B (ENSG00000188064)

Protein

Protein identifiers

Protein Wnt-5a — P41221 (reviewed: P41221)

All UniProt accessions (3): A0A384N611, C9J8I8, P41221

UniProt curated annotations — full annotation on UniProt →

Function. Ligand for members of the frizzled family of seven transmembrane receptors. Can activate or inhibit canonical Wnt signaling, depending on receptor context. In the presence of FZD4, activates beta-catenin signaling. In the presence of ROR2, inhibits the canonical Wnt pathway by promoting beta-catenin degradation through a GSK3-independent pathway which involves down-regulation of beta-catenin-induced reporter gene expression. Suppression of the canonical pathway allows chondrogenesis to occur and inhibits tumor formation. Stimulates cell migration. Decreases proliferation, migration, invasiveness and clonogenicity of carcinoma cells and may act as a tumor suppressor. Mediates motility of melanoma cells. Required during embryogenesis for extension of the primary anterior-posterior axis and for outgrowth of limbs and the genital tubercle. Inhibits type II collagen expression in chondrocytes.

Subunit / interactions. Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity. The complex with AFM may represent the physiological form in body fluids. Homooligomer; disulfide-linked, leading to inactivation (in vitro). Interacts with PORCN. Interacts with WLS. Interacts with glypican GCP3. Interacts with PKD1 (via extracellular domain). Interacts with TMEM67.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expression is increased in differentiated thyroid carcinomas compared to normal thyroid tissue and anaplastic thyroid tumors where expression is low or undetectable. Expression is found in thyrocytes but not in stromal cells (at protein level). Detected in neonate heart and lung.

Post-translational modifications. Glycosylation is necessary for secretion but not for activity. Palmitoleoylation is required for efficient binding to frizzled receptors. Depalmitoleoylation leads to Wnt signaling pathway inhibition. Proteolytic processing by TIKI1 and TIKI2 promotes oxidation and formation of large disulfide-bond oligomers, leading to inactivation of WNT5A.

Disease relevance. Robinow syndrome, autosomal dominant 1 (DRS1) [MIM:180700] A disease characterized by short-limb dwarfism, costovertebral segmentation defects and abnormalities of the head, face and external genitalia. The clinical signs are generally milder in dominant cases. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Wnt family.

Isoforms (2)

UniProt ID	Names	Canonical?
P41221-1	1	yes
P41221-2	2

RefSeq proteins (4): NP_001243034, NP_001364200, NP_001364201, NP_003383* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005817	Wnt	Family
IPR018161	Wnt_CS	Conserved_site
IPR043158	Wnt_C	Homologous_superfamily

Pfam: PF00110

UniProt features (24 total): disulfide bond 11, sequence variant 4, glycosylation site 4, signal peptide 1, propeptide 1, splice variant 1, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41221-F1	88.23	0.78

Functional residue map

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

Post-translational modifications (1): 244

Disulfide bonds (11): 164–182, 238–252, 240–247, 309–340, 325–335, 339–379, 355–370, 357–367, 362–363, 104–115, 154–162

Glycosylation sites (4): 114, 120, 312, 326

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-3238698	WNT ligand biogenesis and trafficking
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-3772470	Negative regulation of TCF-dependent signaling by WNT ligand antagonists
R-HSA-4086398	Ca2+ pathway
R-HSA-4086400	PCP/CE pathway
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-5099900	WNT5A-dependent internalization of FZD4
R-HSA-5140745	WNT5A-dependent internalization of FZD2, FZD5 and ROR2
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9673324	WNT5:FZD7-mediated leishmania damping

MSigDB gene sets: 0 (showing top):

GO Biological Process (171): establishment of planar polarity (GO:0001736), somitogenesis (GO:0001756), kidney development (GO:0001822), epithelial to mesenchymal transition (GO:0001837), neural tube closure (GO:0001843), positive regulation of endothelial cell proliferation (GO:0001938), heart looping (GO:0001947), positive regulation of mesenchymal cell proliferation (GO:0002053), lens development in camera-type eye (GO:0002088), positive regulation of cytokine production involved in immune response (GO:0002720), primary heart field specification (GO:0003138), secondary heart field specification (GO:0003139), ventricular septum development (GO:0003281), atrial septum development (GO:0003283), type B pancreatic cell development (GO:0003323), pericardium morphogenesis (GO:0003344), optic cup formation involved in camera-type eye development (GO:0003408), inflammatory response (GO:0006954), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), Wnt signaling pathway, calcium modulating pathway (GO:0007223), JNK cascade (GO:0007254), axon guidance (GO:0007411), hindgut morphogenesis (GO:0007442), midgut development (GO:0007494), intracellular protein localization (GO:0008104), fibroblast growth factor receptor signaling pathway (GO:0008543), male gonad development (GO:0008584), anterior/posterior axis specification, embryo (GO:0008595), mesenchymal cell proliferation (GO:0010463), positive regulation of endothelial cell migration (GO:0010595), positive regulation of gene expression (GO:0010628), epithelial cell migration (GO:0010631), macrophage derived foam cell differentiation (GO:0010742), positive regulation of T cell chemotaxis (GO:0010820), positive regulation of neuron projection development (GO:0010976), Wnt signaling pathway (GO:0016055), olfactory bulb interneuron development (GO:0021891), neuron differentiation (GO:0030182), keratinocyte differentiation (GO:0030216), lung development (GO:0030324)

GO Molecular Function (9): frizzled binding (GO:0005109), receptor tyrosine kinase-like orphan receptor binding (GO:0005115), cytokine activity (GO:0005125), phospholipid binding (GO:0005543), protein domain specific binding (GO:0019904), receptor ligand activity (GO:0048018), chemoattractant activity involved in axon guidance (GO:1902379), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (13): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), cell surface (GO:0009986), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), Schaffer collateral - CA1 synapse (GO:0098685), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
PCP/CE pathway	3
Signaling by WNT	2
Beta-catenin independent WNT signaling	2
GPCR ligand binding	1
TCF dependent signaling in response to WNT	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Killing mechanisms	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
synapse	3
anatomical structure formation involved in morphogenesis	2
heart field specification	2
cardiac septum development	2
signaling receptor binding	2
protein binding	2
intracellular organelle lumen	2
morphogenesis of a polarized epithelium	1
establishment of tissue polarity	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
somite development	1
animal organ development	1
renal system development	1
mesenchymal cell differentiation	1
primary neural tube formation	1
tube closure	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
camera-type eye development	1
anatomical structure development	1
positive regulation of cytokine production	1
cytokine production involved in immune response	1
positive regulation of production of molecular mediator of immune response	1
regulation of cytokine production involved in immune response	1
cardiac ventricle development	1
cardiac atrium development	1
epithelial cell development	1
type B pancreatic cell differentiation	1
morphogenesis of an epithelial sheet	1
embryonic morphogenesis	1
pericardium development	1

Protein interactions and networks

STRING

3660 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WNT5A	FZD5	Q13467	998
WNT5A	FZD4	Q9ULV1	998
WNT5A	FZD2	Q14332	997
WNT5A	FZD3	Q9NPG1	995
WNT5A	RYK	P34925	995
WNT5A	FZD9	O00144	994
WNT5A	ROR2	Q01974	994
WNT5A	RORA	P35397	992
WNT5A	FZD6	O60353	991
WNT5A	ROR1	Q01973	988
WNT5A	PTK7	Q13308	981
WNT5A	FZD7	O75084	980
WNT5A	LRP5	O75197	980
WNT5A	FZD1	Q9UP38	955
WNT5A	DVL1	O14640	919

IntAct

57 interactions, top by confidence:

A	B	Type	Score
SNX8	POR	psi-mi:“MI:0914”(association)	0.640
FZD7	LRP6	psi-mi:“MI:0914”(association)	0.620
WNT5A	WLS	psi-mi:“MI:0915”(physical association)	0.560
TRAPPC2L	TRAPPC13	psi-mi:“MI:0914”(association)	0.560
KLRG2	GXYLT2	psi-mi:“MI:0914”(association)	0.530
ANTXR1	POTEF	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
PLA2G10	CHEK1	psi-mi:“MI:0914”(association)	0.530
WNT16	WNT11	psi-mi:“MI:0914”(association)	0.530
WNT7A	LDLR	psi-mi:“MI:0914”(association)	0.530
LDLRAD1	ADAM10	psi-mi:“MI:0914”(association)	0.530
TRABD2B	WNT5A	psi-mi:“MI:0194”(cleavage reaction)	0.520
FZD7	TRABD2B	psi-mi:“MI:0914”(association)	0.520
TRABD2B	FZD7	psi-mi:“MI:0914”(association)	0.520
FZD7	TRABD2B	psi-mi:“MI:0194”(cleavage reaction)	0.520
FMR1	ACOT7	psi-mi:“MI:0914”(association)	0.500
WIF1	WNT5A	psi-mi:“MI:0407”(direct interaction)	0.440
WNT5A	ROR1	psi-mi:“MI:0915”(physical association)	0.400
WNT5A	AFM	psi-mi:“MI:0915”(physical association)	0.400
	VWA8	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
FZD7	LRP5	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
NOTCH2	ZNF320	psi-mi:“MI:0914”(association)	0.350
TCTN2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (82): WNT5A (Affinity Capture-MS), WNT5A (Affinity Capture-MS), WNT5A (Affinity Capture-MS), FZD5 (Co-localization), WNT5B (Affinity Capture-MS), WNT5A (Affinity Capture-MS), WNT5A (Affinity Capture-MS), WLS (Affinity Capture-MS), WNT5A (Affinity Capture-MS), WNT5A (Affinity Capture-MS), WNT5A (Affinity Capture-MS), SDF2L1 (Affinity Capture-MS), WNT5A (Affinity Capture-MS), WNT5A (Affinity Capture-MS), WNT5A (Affinity Capture-MS)

ESM2 similar proteins: B2GUT4, O00744, O13267, O42237, O73864, O96014, P04426, P04628, P09615, P10108, P10600, P17125, P21551, P22724, P22725, P22726, P24257, P31286, P33945, P41221, P43446, P47793, P48614, P48615, P49337, P49338, P49339, P49340, P49893, P51891, P56705, P70275, P87387, Q06442, Q06443, Q07258, Q27Q52, Q28J82, Q4VC17, Q5NVK2

Diamond homologs: A0M8S1, A0M8T2, A1X153, A4D7S0, B2GUT4, O00755, O13267, O15978, O42122, O70283, P04426, P04628, P09544, P09615, P10108, P17553, P21551, P21552, P22724, P22725, P22726, P22727, P24257, P24383, P27467, P28047, P28465, P31285, P31286, P33945, P34888, P34889, P41221, P43446, P47793, P49337, P49338, P49339, P49340, P49893

SIGNOR signaling

33 interactions.

A	Effect	B	Mechanism
WNT5A	“up-regulates activity”	FZD3	binding
WNT5A	“up-regulates activity”	LRP6	binding
WNT5A	“up-regulates activity”	FZD6	binding
WNT5A	down-regulates	AXIN1
WNT5A	“up-regulates activity”	DVL1
WNT5A	up-regulates	GSK3B
WNT5A	up-regulates	ROR1	binding
WNT5A	down-regulates	FZD2	binding
GPC4	up-regulates	WNT5A	binding
WNT5A	up-regulates	ROR2	binding
WNT5A	down-regulates	GSK3B/Axin/APC
WNT5A	“down-regulates activity”	GSK3B/Axin/APC
WNT5A	“up-regulates activity”	Frizzled	binding
WNT5A	“up-regulates activity”	FZD2	binding
WNT5A	“up-regulates activity”	FZD4	binding
WNT5A	up-regulates	RYK	binding
GPC6	“down-regulates activity”	WNT5A	binding
GLIS1	“up-regulates quantity by expression”	WNT5A	“transcriptional regulation”
hsa-miR-26a-5p	“down-regulates quantity by repression”	WNT5A	“post transcriptional regulation”
miR-139-3p	“down-regulates quantity by destabilization”	WNT5A	“post transcriptional regulation”
WNT5A	up-regulates	FZD5	binding
WNT5A	“up-regulates activity”	MYOD1
SOSTDC1	“down-regulates activity”	WNT5A
NFIA	“down-regulates quantity”	WNT5A	“transcriptional regulation”
NFIB	“down-regulates quantity”	WNT5A	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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
WNT ligand biogenesis and trafficking	6	47.9×	5e-07
Class B/2 (Secretin family receptors)	6	21.6×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
canonical Wnt signaling pathway	8	17.5×	1e-05
Wnt signaling pathway	7	10.0×	2e-03
neuron differentiation	6	8.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	8
Uncertain significance	147
Likely benign	92
Benign	22

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1065560	NM_003392.7(WNT5A):c.206G>T (p.Cys69Phe)	Pathogenic
162612	NM_003392.7(WNT5A):c.257A>G (p.Tyr86Cys)	Pathogenic
29820	NM_003392.7(WNT5A):c.248G>C (p.Cys83Ser)	Pathogenic
1025097	NM_003392.7(WNT5A):c.991G>T (p.Gly331Cys)	Likely pathogenic
29819	NM_003392.7(WNT5A):c.544T>C (p.Cys182Arg)	Likely pathogenic
3347185	NM_003392.7(WNT5A):c.830G>C (p.Arg277Pro)	Likely pathogenic
3776042	NM_003392.7(WNT5A):c.247T>C (p.Cys83Arg)	Likely pathogenic
4278181	NM_003392.7(WNT5A):c.583_584delinsAG (p.Glu195Arg)	Likely pathogenic
488060	NM_003392.7(WNT5A):c.479C>G (p.Ser160Cys)	Likely pathogenic
981471	NM_003392.7(WNT5A):c.248G>A (p.Cys83Tyr)	Likely pathogenic
981473	NM_003392.7(WNT5A):c.247T>G (p.Cys83Gly)	Likely pathogenic

SpliceAI

1218 predictions. Top by Δscore:

Variant	Effect	Δscore
3:55470041:T:A	donor_gain	1.0000
3:55470092:CTA:C	donor_gain	1.0000
3:55474330:CACT:C	donor_loss	1.0000
3:55474331:ACTC:A	donor_loss	1.0000
3:55474332:CTCA:C	donor_loss	1.0000
3:55474333:TCACC:T	donor_loss	1.0000
3:55474334:CA:C	donor_loss	1.0000
3:55474335:A:AC	donor_gain	1.0000
3:55474335:A:T	donor_loss	1.0000
3:55474335:AC:A	donor_gain	1.0000
3:55474336:C:CC	donor_gain	1.0000
3:55474336:C:CG	donor_loss	1.0000
3:55474336:CC:C	donor_gain	1.0000
3:55474336:CCCTG:C	donor_gain	1.0000
3:55480784:CCA:C	donor_gain	1.0000
3:55480916:CTT:C	acceptor_gain	1.0000
3:55470092:C:CT	donor_gain	0.9900
3:55470093:T:TT	donor_gain	0.9900
3:55470097:TGC:T	donor_gain	0.9900
3:55470097:TGCAC:T	donor_gain	0.9900
3:55470098:G:A	donor_gain	0.9900
3:55470547:CCGT:C	acceptor_gain	0.9900
3:55470548:CGTC:C	acceptor_gain	0.9900
3:55470551:C:CC	acceptor_gain	0.9900
3:55474329:GCACT:G	donor_loss	0.9900
3:55474336:CCCT:C	donor_gain	0.9900
3:55474626:CTGC:C	acceptor_gain	0.9900
3:55474627:TGC:T	acceptor_gain	0.9900
3:55474628:GCCT:G	acceptor_loss	0.9900
3:55474630:C:CC	acceptor_gain	0.9900

AlphaMissense

2516 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:55470098:G:C	C379W	1.000
3:55470099:C:A	C379F	1.000
3:55470099:C:G	C379S	1.000
3:55470099:C:T	C379Y	1.000
3:55470100:A:G	C379R	1.000
3:55470100:A:T	C379S	1.000
3:55470126:C:G	C370S	1.000
3:55470127:A:T	C370S	1.000
3:55470134:G:C	C367W	1.000
3:55470135:C:A	C367F	1.000
3:55470135:C:G	C367S	1.000
3:55470135:C:T	C367Y	1.000
3:55470136:A:G	C367R	1.000
3:55470136:A:T	C367S	1.000
3:55470141:A:T	V365D	1.000
3:55470146:G:C	C363W	1.000
3:55470147:C:A	C363F	1.000
3:55470147:C:G	C363S	1.000
3:55470147:C:T	C363Y	1.000
3:55470148:A:G	C363R	1.000
3:55470148:A:T	C363S	1.000
3:55470149:G:C	C362W	1.000
3:55470150:C:A	C362F	1.000
3:55470150:C:G	C362S	1.000
3:55470150:C:T	C362Y	1.000
3:55470151:A:G	C362R	1.000
3:55470151:A:T	C362S	1.000
3:55470152:C:A	W361C	1.000
3:55470152:C:G	W361C	1.000
3:55470154:A:G	W361R	1.000

dbSNP variants (sampled 300 via entrez): RS1000015417 (3:55495231 A>C), RS1000020143 (3:55497873 G>A), RS1000177895 (3:55477093 A>G), RS1000193758 (3:55501803 A>G), RS1000383319 (3:55485666 G>C), RS1000404242 (3:55473048 A>G), RS1000481834 (3:55472765 T>A,C), RS1000488645 (3:55479807 C>T), RS1000494080 (3:55491135 G>A), RS1000531416 (3:55502112 A>G), RS1000574438 (3:55503232 G>T), RS1000602752 (3:55506655 G>A), RS1000631899 (3:55506376 T>C), RS1000718552 (3:55471719 C>A), RS1000972864 (3:55500207 C>A)

Disease associations

OMIM: gene MIM:164975 | disease phenotypes: MIM:180700, MIM:618878

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant Robinow syndrome 1	Definitive	Autosomal dominant
autosomal dominant Robinow syndrome	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal dominant Robinow syndrome	Moderate	AD

Mondo (3): autosomal dominant Robinow syndrome 1 (MONDO:0024455), autosomal dominant Robinow syndrome (MONDO:0008389), leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (MONDO:0030036)

Orphanet (2): Autosomal dominant Robinow syndrome (Orphanet:3107), Robinow syndrome (Orphanet:97360)

HPO phenotypes

116 total (30 of 116 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000036	Abnormal penis morphology
HP:0000039	Epispadias
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000075	Renal duplication
HP:0000126	Hydronephrosis
HP:0000158	Macroglossia
HP:0000168	Abnormality of the gingiva
HP:0000189	Narrow palate
HP:0000200	Short lingual frenulum
HP:0000202	Orofacial cleft
HP:0000207	Triangular mouth
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004185_10	Lung function (FEV1/FVC)	4.000000e-10
GCST005351_16	Carboplatin disposition in epthelial ovarian cancer	9.000000e-06
GCST006484_9	Type 2 diabetes	8.000000e-07
GCST008163_109	Height	7.000000e-06
GCST009391_1705	Metabolite levels	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0010340	cholesteryl ester 14:0 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, decreases reaction, affects cotreatment, increases expression	6
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	6
Valproic Acid	affects cotreatment, increases expression	5
bisphenol A	affects cotreatment, decreases methylation, decreases expression	3
trichostatin A	increases expression, decreases expression, affects cotreatment	3
sodium arsenite	decreases expression, increases expression	3
monomethylarsonous acid	affects expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	3
(+)-JQ1 compound	decreases expression	3
Air Pollutants	affects cotreatment, affects expression, increases abundance, decreases expression	3
Benzo(a)pyrene	decreases methylation, increases expression	3
Silicon Dioxide	decreases expression	3
Tobacco Smoke Pollution	affects expression, increases expression, affects response to substance	3
Tretinoin	decreases reaction, affects cotreatment, decreases expression, increases reaction, increases expression	3
Cyclosporine	decreases expression, increases expression	3
arsenite	increases expression, decreases expression, decreases reaction	2
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
hydroquinone	increases expression, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
bisphenol S	decreases expression, increases expression, affects reaction	2
Resveratrol	affects cotreatment, decreases expression	2
Temozolomide	decreases expression, affects response to substance	2
Fulvestrant	decreases expression, decreases reaction, increases expression, affects cotreatment, decreases methylation	2
Panobinostat	affects cotreatment, decreases expression	2
Aluminum Hydroxide	affects cotreatment, decreases expression, increases reaction, decreases reaction	2
Chelating Agents	affects binding, increases expression	2
Cisplatin	decreases expression, decreases response to substance, increases expression, affects cotreatment	2
Copper	affects binding, increases expression	2
Lipopolysaccharides	decreases reaction, increases expression, affects response to substance, affects cotreatment	2

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8JY	UACC-1273-4-3	Cancer cell line	Male
CVCL_A8JZ	UACC-1273-4-7	Cancer cell line	Male
CVCL_B2LG	Abcam HeLa WNT5A KO	Cancer cell line	Female
CVCL_B7HX	NSG-70-WNT5A-GFP	Cancer cell line	Male
CVCL_B9U9	Abcam A-549 WNT5A KO	Cancer cell line	Male
CVCL_D9VU	Ubigene HEK293 WNT5A KO	Transformed cell line	Female
CVCL_XE50	K562-Wnt5a	Cancer cell line	Female

Clinical trials (associated diseases)

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