DVL3

Summary

DVL3 (dishevelled segment polarity protein 3, HGNC:3087) is a protein-coding gene on chromosome 3q27.1, encoding Segment polarity protein dishevelled homolog DVL-3 (Q92997). Involved in the signal transduction pathway mediated by multiple Wnt genes.

This gene is a member of a multi-gene family which shares strong similarity with the Drosophila dishevelled gene, dsh. The Drosophila dishevelled gene encodes a cytoplasmic phosphoprotein that regulates cell proliferation.

Source: NCBI Gene 1857 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant Robinow syndrome 3 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 468 total — 9 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 106
• Druggable target: yes
• MANE Select transcript: NM_004423

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3087
Approved symbol	DVL3
Name	dishevelled segment polarity protein 3
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0208
Ensembl gene	ENSG00000161202
Ensembl biotype	protein_coding
OMIM	601368
Entrez	1857

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 24 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000313143, ENST00000423300, ENST00000431765, ENST00000435708, ENST00000462665, ENST00000467873, ENST00000478247, ENST00000478639, ENST00000648288, ENST00000649364, ENST00000649847, ENST00000867758, ENST00000867759, ENST00000867760, ENST00000867761, ENST00000867762, ENST00000867763, ENST00000867764, ENST00000867765, ENST00000867766, ENST00000921743, ENST00000921744, ENST00000921745, ENST00000945025, ENST00000945026, ENST00000945027, ENST00000945028, ENST00000945029, ENST00000945030, ENST00000945031, ENST00000945032, ENST00000945033, ENST00000945034

RefSeq mRNA: 1 — MANE Select: NM_004423 NM_004423

CCDS: CCDS3253

Canonical transcript exons

ENST00000313143 — 15 exons

Exon	Start	End
ENSE00001056847	184164796	184164931
ENSE00001056855	184165113	184165206
ENSE00001914714	184155377	184155796
ENSE00003462214	184166826	184166975
ENSE00003477344	184164267	184164388
ENSE00003492931	184166446	184166522
ENSE00003498393	184167580	184167711
ENSE00003519076	184166606	184166673
ENSE00003530614	184164492	184164601
ENSE00003579336	184170006	184170221
ENSE00003606286	184167898	184168065
ENSE00003609474	184163657	184163726
ENSE00003639698	184165422	184165491
ENSE00003693237	184166126	184166265
ENSE00003835677	184170319	184173614

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 96.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8931 / max 297.4962, expressed in 1812 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40126	15.6629	1801
40127	8.2607	1733
40128	0.6843	409
40125	0.2853	131

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	96.48	gold quality
ganglionic eminence	UBERON:0004023	96.38	gold quality
mucosa of stomach	UBERON:0001199	95.93	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.43	gold quality
lower esophagus	UBERON:0013473	95.42	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.39	gold quality
endometrium epithelium	UBERON:0004811	95.31	gold quality
body of uterus	UBERON:0009853	95.22	gold quality
metanephros cortex	UBERON:0010533	95.21	gold quality
apex of heart	UBERON:0002098	95.12	gold quality
sural nerve	UBERON:0015488	95.10	gold quality
right ovary	UBERON:0002118	95.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.09	gold quality
left uterine tube	UBERON:0001303	94.90	gold quality
left ovary	UBERON:0002119	94.88	gold quality
cortical plate	UBERON:0005343	94.77	gold quality
endocervix	UBERON:0000458	94.69	gold quality
left lobe of thyroid gland	UBERON:0001120	94.45	gold quality
right coronary artery	UBERON:0001625	94.43	gold quality
adenohypophysis	UBERON:0002196	94.38	gold quality
ventricular zone	UBERON:0003053	94.33	gold quality
popliteal artery	UBERON:0002250	94.26	gold quality
tibial artery	UBERON:0007610	94.26	gold quality
right lobe of thyroid gland	UBERON:0001119	94.20	gold quality
ectocervix	UBERON:0012249	94.10	gold quality
right atrium auricular region	UBERON:0006631	93.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.92	gold quality
cardiac atrium	UBERON:0002081	93.75	gold quality
aorta	UBERON:0000947	93.69	gold quality
thyroid gland	UBERON:0002046	93.66	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	229.42
E-ANND-3	yes	6.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

194 targeting DVL3, 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-6758-5P	100.00	66.21	1470
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-10401-5P	99.99	65.79	948
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784

Literature-anchored findings (GeneRIF, showing 40)

• Regulation of hemocytes in Drosophila requires dappled cytochrome b5 (PMID:21279680)
• The facilitation of Prickle-1 on Dvl3 degradation and the suppression of beta-catenin activity and cell growth suggest that Prickle-1 is a negative regulator of the Wnt/beta-catenin signaling pathway (PMID:17030191)
• The expression of Dishevelleds in mammalian cells provide an estimate of the relative cellular abundance of each Dvl. (PMID:18093802)
• Expression of Dvl-1, Dvl-2 and Dvl-3, is common in non-small cell lung cancer (PMID:18692936)
• The canonical Wnt-signaling proteins LRP6 and Dvl2 and Dvl3 are involved in the regulation of beta-catenin. (PMID:20137080)
• In HEK293T cells with intact Wnt signaling, Rac1b is tethered to these same gene promoters independent of Wnt3A stimulation and is further observed to recruit Dishevelled and beta-catenin in the absence of Wnt3A stimulation. (PMID:21667018)
• Letter: report expression of dishevelled-3 and EAAT1 and glutamine metabolism in malignant pleural mesothelioma. (PMID:22569537)
• Identification of novel post translational modifications of DVL3 by liquid chromatography coupled LTQ-Orbitrap analysis. (PMID:22612246)
• A harmful p.Ser175Gly substitution & 3 benign variants (p.Ile353Val, p.Ile384Val, & p.Ala641Thr) were found in a cohort of patients with neural tube defects but not in controls. (PMID:22892949)
• Dvl3 protein transduce signals via the Wnt proteins non canonical pathways, namely via NFAT protein and Src kinase and novel NPM-ALK interacting proteins and possibly NPM-ALK substrates. (PMID:23022960)
• AMPK activators suppress cervical cancer cell growth by impairing DVL3 protein synthesis via AMPK/mTOR signaling and/or partially promoting the proteasomal degradation of DVL3 (PMID:23301094)
• Study showed an association of DVL-1 and DVL-3 with Hirschsprung’s disease. (PMID:24040443)
• High expression of IGFBP7 in fibroblasts induced by colorectal cancer cells is co-regulated by TGF-beta and Wnt signaling in a Smad2/3-Dvl2/3-dependent manner. (PMID:24427302)
• data (i) support previous the assumption that CK1 acts via phosphorylation of distinct residues as the activator as well as the shut-off signal of Wnt/beta-catenin signaling and (ii) suggest that CK1 acts on Dvl via different mechanism than Fzd5. (PMID:24993822)
• findings confirm that p38 and PAX2 are important for the Dvl-3 induced upregulation of p120ctn (PMID:25156800)
• Tumors that responded to IGFIR inhibition contain relatively lower levels of DVL3 protein than resistant tumors. (PMID:25168481)
• data suggest that miR-204-5p regulates adipogenesis by controlling DVL3 expression and subsequently inhibiting the activation of the Wnt/beta-catenin signaling pathway. (PMID:25847080)
• DVL3 transcripts decreased in individuals with major depressive disorder (PMID:26008736)
• Kif26b, together with Dvl3/Daam1, initiates cell polarity through the control of planar cell polarity-signaling pathway-dependent activation in endothelial cells. (PMID:26792835)
• All variants in DVL3 result in a -1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. (PMID:26924530)
• we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. (PMID:27008544)
• Data show that dishevelled proteins DVL1, 2 and 3 were exclusively expressed in chronic lymphatic leukaemia (CLL) cells as compared to normal peripheral blood mononuclear cells (PBMCs). (PMID:27086035)
• two mutually exclusive functions of the DEP domain in Wnt signal transduction - binding to Frizzled to recruit Dishevelled to the receptor complex, is reported. (PMID:27744318)
• Studied and identified candidate biomarkers of biochemical recurrence (BCR) of prostate adenocarcinoma by integrating reverse-phase protein array (RPPA) and mRNA datafrom The Cancer Genome Atlas (TCGA). Found DVL3 was expressed in patients with a higher risk of BCR. DVL3 may be a novel and easily applicable recurrence predictor of localised prostate adenocarcinoma. (PMID:28107606)
• we found that Wnt3a treatment rapidly induces hyperphosphorylation and stabilization of Dvl2 and Dvl3. Our findings suggest a model of positive regulation of PKCzeta-mediated Dvl signaling activity, to produce a strong and sustained response to Wnt3a treatment by stabilizing Dvl protein levels. (PMID:28366812)
• Dvl3 is overexpressed in human HCCs. The NP-Dvl3 is the more stable and active form of the protein and enhances HCC stemness. (PMID:28455968)
• Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). (PMID:28705114)
• These findings expand the clinical spectrum of Robinow syndrome associated with DVL3 mutations. To date, comparison of clinical data of DVL3 mutation-positive individuals with those of patients with genetically different forms did not allow delineation of gene-specific phenotypes. (PMID:29575616)
• The interaction between Dvl3 allelic variations and negative life events. (PMID:30242173)
• downregulation of ASPM expression pronouncedly attenuated the proliferation, colony formation, and the invasive behavior of PCA cells, and dramatically reduced the number of ALDH(+) CSCs and inhibited cancer stemness and tumorigenicity. Mechanistically, ASPM interacts with disheveled-3 (Dvl-3), a cardinal upstream regulator of canonical Wnt signaling, and inhibits its proteasome-dependent degradation (PMID:30266990)
• down-regulation of Dvl3 expression can control the progression of esophageal squamous cell carcinoma, inhibit the growth and promote the apoptosis of tumor cells (PMID:30536315)
• In silico modeling and in vitro biophysical methods explain how CK1epsilon-specific phosphorylation events control conformational dynamics of DVL3 in living cells upon Wnt pathway stimulation via modulation of the PDZ domain and its interaction with DVL3 C-terminus. (PMID:31000703)
• The NEK2 triggered phosphorylation of PDZ domain at S263 and S280 prevents binding of DVL3 C-terminus to PDZ and promotes an open conformation of DVL3 that is more prone to even subcellular localization. (PMID:31870452)
• Silencing DVL3 defeats MTX resistance and attenuates stemness via Notch Signaling Pathway in colorectal cancer. (PMID:32414668)
• DVL mutations identified from human neural tube defects and Dandy-Walker malformation obstruct the Wnt signaling pathway. (PMID:32900645)
• Polymorphism and expression of the Dvl3 gene in the etiology of depressive disorder.", trans “Znaczenie polimorfizmu i ekspresji genu Dvl3 w etiologii zaburzen depresyjnych nawracajacych. (PMID:33038884)
• Clinical and molecular characterization of four patients with Robinow syndrome from different families. (PMID:33496066)
• The Gender-Specific Interaction of DVL3 and GSK3beta Polymorphisms on Major Depressive Disorder Susceptibility in a Chinese Han Population: A Case-Control Study. (PMID:35126809)
• Circ_0101802 Facilitates Colorectal Cancer Progression Depending on the Regulation of miR-665/DVL3 Signaling. (PMID:35314912)
• Exosomal Dvl3 promoted the aggressive phenotypic transformation of RA-FLS via wnt pathway. (PMID:35499309)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	dvl3a	ENSDARG00000015707
danio_rerio	dvl3b	ENSDARG00000103462
mus_musculus	Dvl3	ENSMUSG00000003233
rattus_norvegicus	Dvl3	ENSRNOG00000001708
drosophila_melanogaster	dsh	FBGN0000499
caenorhabditis_elegans		WBGENE00001101
caenorhabditis_elegans		WBGENE00001102
caenorhabditis_elegans		WBGENE00003241

Paralogs (3): DVL2 (ENSG00000004975), DVL1 (ENSG00000107404), DIXDC1 (ENSG00000150764)

Protein

Protein identifiers

Segment polarity protein dishevelled homolog DVL-3 — Q92997 (reviewed: Q92997)

Alternative names: DSH homolog 3

All UniProt accessions (4): A0A3B3ISG4, A0A3B3ITC6, Q92997, F8WCF1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the signal transduction pathway mediated by multiple Wnt genes.

Subunit / interactions. Interacts (via the PDZ domain) with the C-terminal regions of VANGL1 and VANGL2. Interacts (via the region containing both the PDZ and DEP domains) with LRRFIP2; the DIX domain may inhibit this interaction. Interacts with CYLD, CEP164 and DAB2. Interacts with DCDC2. Interacts with FOXK1 and FOXK2. Interacts with DAAM2.

Subcellular location. Cytoplasm.

Post-translational modifications. Ubiquitinated. Deubiquitinated by CYLD, which acts on ‘Lys-63’-linked ubiquitin chains. Phosphorylated by CSNK1D. Arginine methylation may function as a switch in regulation of function in Wnt signaling.

Disease relevance. Robinow syndrome, autosomal dominant 3 (DRS3) [MIM:616894] A form of Robinow syndrome, a rare skeletal dysplasia syndrome characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, genital hypoplasia, renal anomalies, and costovertebral segmentation defects. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DSH family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92997-1	1	yes
Q92997-2	2

RefSeq proteins (1): NP_004414* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000591	DEP_dom	Domain
IPR001158	DIX	Domain
IPR001478	PDZ	Domain
IPR003351	Dishevelled_protein_dom	Domain
IPR008339	Dishevelled_fam	Family
IPR008342	DVL3	Family
IPR015506	Dsh/Dvl-rel	Family
IPR024580	Dishevelled_C-dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR038207	DIX_dom_sf	Homologous_superfamily

Pfam: PF00595, PF00610, PF00778, PF02377, PF12316

UniProt features (69 total): sequence conflict 22, modified residue 15, compositionally biased region 8, strand 8, domain 3, mutagenesis site 3, helix 3, sequence variant 2, region of interest 2, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8S6A	X-RAY DIFFRACTION	1.36
6ZBQ	X-RAY DIFFRACTION	1.43
6ZC7	X-RAY DIFFRACTION	1.48
6ZC6	X-RAY DIFFRACTION	1.58
6ZBZ	X-RAY DIFFRACTION	1.6
6ZC3	X-RAY DIFFRACTION	1.67
6ZC4	X-RAY DIFFRACTION	1.85
6ZC8	X-RAY DIFFRACTION	2.76
6V7O	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92997-F1	59.50	0.20

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 (15): 27, 48, 125, 192, 212, 271, 271, 342, 342, 346, 614, 697, 698, 698, 700

Mutagenesis-validated functional residues (3):

Position	Phenotype
271	localizes to plasma membranes.
342	no effect on subcellular location.
614	localizes to plasma membranes.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-201688	WNT mediated activation of DVL
R-HSA-4086400	PCP/CE pathway
R-HSA-4641258	Degradation of DVL
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane
R-HSA-5368598	Negative regulation of TCF-dependent signaling by DVL-interacting proteins
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-9673324	WNT5:FZD7-mediated leishmania damping

MSigDB gene sets: 488 (showing top): TAATAAT_MIR126, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GCANCTGNY_MYOD_Q6, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, HSIAO_HOUSEKEEPING_GENES, GOBP_NEUROGENESIS, GOMF_GTPASE_BINDING, CAGCTG_AP4_Q5, SRF_Q5_01, PATIL_LIVER_CANCER, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, SRF_C, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION

GO Biological Process (14): small GTPase-mediated signal transduction (GO:0007264), response to xenobiotic stimulus (GO:0009410), regulation of protein localization (GO:0032880), regulation of actin cytoskeleton organization (GO:0032956), non-canonical Wnt signaling pathway (GO:0035567), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), protein stabilization (GO:0050821), canonical Wnt signaling pathway (GO:0060070), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), positive regulation of neuron projection arborization (GO:0150012), Wnt signaling pathway (GO:0016055), intracellular signal transduction (GO:0035556)

GO Molecular Function (6): protease binding (GO:0002020), signaling receptor binding (GO:0005102), frizzled binding (GO:0005109), beta-catenin binding (GO:0008013), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	4
Signaling by WNT	1
Beta-catenin independent WNT signaling	1
RHO GTPase Effectors	1
Killing mechanisms	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
Wnt signaling pathway	2
intracellular anatomical structure	2
protein binding	2
intracellular signaling cassette	1
response to chemical	1
intracellular protein localization	1
regulation of localization	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
regulation of protein stability	1
non-canonical Wnt signaling pathway	1
positive regulation of cell projection organization	1
positive regulation of developmental process	1
neuron projection arborization	1
regulation of neuron projection arborization	1
cell surface receptor signaling pathway	1
signal transduction	1
enzyme binding	1
G protein-coupled receptor binding	1
GTPase binding	1
binding	1
chromosome	1
cytoplasm	1

Protein interactions and networks

STRING

1847 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DVL3	FZD7	O75084	880
DVL3	DAB2	P98082	877
DVL3	VANGL2	Q9ULK5	871
DVL3	FZD4	Q9ULV1	828
DVL3	WNT5A	P41221	815
DVL3	VANGL1	Q8TAA9	796
DVL3	WNT3A	P56704	763
DVL3	FZD6	O60353	758
DVL3	LRP6	O75581	748
DVL3	DACT1	Q9NYF0	733
DVL3	CEP164	Q9UPV0	719
DVL3	AXIN1	O15169	714
DVL3	ADAR	P55265	712
DVL3	FZD5	Q13467	700
DVL3	FZD8	Q9H461	684

IntAct

997 interactions, top by confidence:

A	B	Type	Score
DVL3	CSNK1E	psi-mi:“MI:0915”(physical association)	0.810
CSNK1E	DVL3	psi-mi:“MI:0915”(physical association)	0.810
TUBG1	TUBG1	psi-mi:“MI:2364”(proximity)	0.760
SYT6	DVL3	psi-mi:“MI:0915”(physical association)	0.720
YTHDC1	DVL3	psi-mi:“MI:0915”(physical association)	0.720
DVL3	SYT6	psi-mi:“MI:0915”(physical association)	0.720
DVL3	LNX1	psi-mi:“MI:0915”(physical association)	0.690
CSNK1D	DVL3	psi-mi:“MI:0915”(physical association)	0.670
DVL3	CSNK1D	psi-mi:“MI:0915”(physical association)	0.670
DVL3	RPL9A	psi-mi:“MI:0915”(physical association)	0.610
RPL9A	DVL3	psi-mi:“MI:0915”(physical association)	0.610
DVL3	ADAP1	psi-mi:“MI:0915”(physical association)	0.560
STOM	DVL3	psi-mi:“MI:0915”(physical association)	0.560
RWDD2B	DVL3	psi-mi:“MI:0915”(physical association)	0.560
KLF3	DVL3	psi-mi:“MI:0915”(physical association)	0.560
ZNF264	DVL3	psi-mi:“MI:0915”(physical association)	0.560
ZNF697	DVL3	psi-mi:“MI:0915”(physical association)	0.560
DVL3	FAM13C	psi-mi:“MI:0915”(physical association)	0.560
DVL3	UTP3	psi-mi:“MI:0915”(physical association)	0.560
DVL3	NXF1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (341): DVL3 (Two-hybrid), DVL3 (Two-hybrid), STOM (Two-hybrid), ZNF264 (Two-hybrid), RWDD2B (Two-hybrid), NXF1 (Two-hybrid), ADAP1 (Two-hybrid), KLF3 (Two-hybrid), UTP3 (Two-hybrid), NOL12 (Two-hybrid), ZNF697 (Two-hybrid), YTHDC1 (Two-hybrid), SYT6 (Two-hybrid), FAM13C (Two-hybrid), WWTR1 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2K2P5, A0JNJ1, B1WAP7, G9CGD6, O14640, O75122, O88382, O95049, O97758, P34908, P39447, P51141, P54792, P70175, Q05AS8, Q07157, Q16825, Q5F488, Q5IS48, Q5SGD7, Q5TCQ9, Q5XI81, Q61062, Q62136, Q62728, Q62936, Q6DKE2, Q6P9H4, Q6ZM86, Q812E4, Q86UL8, Q8BMA3, Q8IVH8, Q8JHI3, Q8TDW5, Q920B0, Q924I2, Q925T6, Q92997, Q95168

Diamond homologs: A0A8C0TYJ0, B1WAP7, G5ECY0, O14640, O14641, O15018, O15169, O35625, O35889, O42400, O54824, O55164, O70239, O70240, O75970, O88566, P31007, P31016, P51140, P51141, P51142, P54792, P55196, P57094, P57105, P70175, P78352, Q05AS8, Q12923, Q12959, Q14005, Q155Q3, Q15700, Q22227, Q28C55, Q2VUH7, Q3T0C9, Q5IS48, Q5PYH5, Q5PYH6

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
NKD1	down-regulates	DVL3	binding
RYK	up-regulates	DVL3	binding
LRRFIP2	up-regulates	DVL3	binding
DVL3	up-regulates	PIP5K1A	binding
SDC4	up-regulates	DVL3	binding
LRRK2	up-regulates	DVL3	binding
KHSRP	down-regulates	DVL3	binding
FZD1	“up-regulates activity”	DVL3	binding
FZD4	“up-regulates activity”	DVL3	binding
FZD2	“up-regulates activity”	DVL3	binding
FZD5	“up-regulates activity”	DVL3	binding
DVL3	“up-regulates activity”	PLCB1
WDFY3	“down-regulates quantity by destabilization”	DVL3	relocalization
DVL3	up-regulates	CSNK1E	binding
DVL3	up-regulates	RAC1	binding
DVL3	up-regulates	FRAT1	binding
CSNK1E	“down-regulates activity”	DVL3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 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
R-HSA-400253	5	26.2×	5e-05
Loss of Nlp from mitotic centrosomes	9	21.6×	3e-08
Loss of proteins required for interphase microtubule organization from the centrosome	9	21.6×	3e-08
AURKA Activation by TPX2	9	20.8×	3e-08
Centrosome maturation	5	19.2×	2e-04
Recruitment of mitotic centrosome proteins and complexes	9	18.5×	7e-08
Regulation of PLK1 Activity at G2/M Transition	9	17.3×	1e-07
Anchoring of the basal body to the plasma membrane	10	17.1×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
mRNA export from nucleus	5	13.9×	3e-03
cilium assembly	8	5.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	10
Uncertain significance	212
Likely benign	162
Benign	35

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
219218	NM_004423.4(DVL3):c.1585del (p.Ala529fs)	Pathogenic
219219	NM_004423.4(DVL3):c.1715-2A>G	Pathogenic
219221	NM_004423.4(DVL3):c.1716del (p.Ser573fs)	Pathogenic
219222	NM_004423.4(DVL3):c.1749del (p.Ser583fs)	Pathogenic
3764613	NM_004423.4(DVL3):c.1672_1705del (p.Tyr558fs)	Pathogenic
689755	NM_004423.4(DVL3):c.1592del (p.Pro531fs)	Pathogenic
694689	NM_004423.4(DVL3):c.1715-2A>C	Pathogenic
817264	NM_004423.4(DVL3):c.1751_1754del (p.Asp584fs)	Pathogenic
817756	NM_004423.4(DVL3):c.1728_1752del (p.Ser578fs)	Pathogenic
1333918	NM_004423.4(DVL3):c.1473C>G (p.Tyr491Ter)	Likely pathogenic
1690811	NM_004423.4(DVL3):c.1760_1763del (p.Lys587fs)	Likely pathogenic
2664033	NM_004423.4(DVL3):c.292del (p.Glu98fs)	Likely pathogenic
3775469	NM_004423.4(DVL3):c.1688dup (p.Ser564fs)	Likely pathogenic
488049	NM_004423.4(DVL3):c.1617del (p.Gln539fs)	Likely pathogenic
627534	NM_004423.4(DVL3):c.367G>A (p.Gly123Arg)	Likely pathogenic
800837	NM_004423.4(DVL3):c.1715-1G>C	Likely pathogenic
814505	GRCh37/hg19 3q27.1-27.3(chr3:183789584-186034649)x1	Likely pathogenic
981469	NM_004423.4(DVL3):c.1715-2del	Likely pathogenic
988465	NM_004423.4(DVL3):c.1745del (p.Gly582fs)	Likely pathogenic

SpliceAI

2534 predictions. Top by Δscore:

Variant	Effect	Δscore
3:184163653:GCA:G	acceptor_loss	1.0000
3:184163655:A:AG	acceptor_gain	1.0000
3:184163655:A:AT	acceptor_loss	1.0000
3:184163655:AGAGT:A	acceptor_gain	1.0000
3:184163656:G:GG	acceptor_gain	1.0000
3:184163656:GA:G	acceptor_gain	1.0000
3:184163656:GAGT:G	acceptor_gain	1.0000
3:184163656:GAGTG:G	acceptor_gain	1.0000
3:184163717:G:GA	donor_gain	1.0000
3:184163723:CTGGG:C	donor_loss	1.0000
3:184163724:TGGG:T	donor_loss	1.0000
3:184163725:GG:G	donor_gain	1.0000
3:184163725:GGGTA:G	donor_loss	1.0000
3:184163726:GG:G	donor_gain	1.0000
3:184163726:GGTA:G	donor_loss	1.0000
3:184163727:G:A	donor_loss	1.0000
3:184163727:G:GG	donor_gain	1.0000
3:184163728:T:G	donor_loss	1.0000
3:184164262:TTCA:T	acceptor_loss	1.0000
3:184164264:CAGCT:C	acceptor_loss	1.0000
3:184164265:A:AG	acceptor_gain	1.0000
3:184164265:AGCT:A	acceptor_gain	1.0000
3:184164265:AGCTG:A	acceptor_gain	1.0000
3:184164266:G:GC	acceptor_gain	1.0000
3:184164266:GC:G	acceptor_gain	1.0000
3:184164266:GCT:G	acceptor_gain	1.0000
3:184164266:GCTG:G	acceptor_gain	1.0000
3:184164266:GCTGG:G	acceptor_gain	1.0000
3:184164355:G:T	donor_gain	1.0000
3:184164384:TTCCA:T	donor_gain	1.0000

AlphaMissense

4738 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:184155657:T:G	Y8D	1.000
3:184155688:T:C	L18P	1.000
3:184155724:T:C	L30S	1.000
3:184155724:T:G	L30W	1.000
3:184155772:T:C	F46S	1.000
3:184155777:T:C	S48P	1.000
3:184163695:T:A	L67Q	1.000
3:184163695:T:C	L67P	1.000
3:184163695:T:G	L67R	1.000
3:184163724:T:A	W77R	1.000
3:184163724:T:C	W77R	1.000
3:184165477:T:A	V250D	1.000
3:184165483:T:A	L252H	1.000
3:184165483:T:C	L252P	1.000
3:184166137:T:A	F259I	1.000
3:184166137:T:C	F259L	1.000
3:184166137:T:G	F259V	1.000
3:184166138:T:C	F259S	1.000
3:184166138:T:G	F259C	1.000
3:184166139:C:A	F259L	1.000
3:184166139:C:G	F259L	1.000
3:184166141:T:C	L260S	1.000
3:184166141:T:G	L260W	1.000
3:184166143:G:A	G261S	1.000
3:184166143:G:C	G261R	1.000
3:184166143:G:T	G261C	1.000
3:184166144:G:A	G261D	1.000
3:184166144:G:C	G261A	1.000
3:184166144:G:T	G261V	1.000
3:184166147:T:A	I262N	1.000

dbSNP variants (sampled 300 via entrez): RS1000058861 (3:184169884 G>A), RS1000299976 (3:184173604 TATTATTATTATTTTATC>T), RS1000431213 (3:184156677 A>T), RS1000446360 (3:184166343 A>C), RS1000780750 (3:184156354 A>G), RS1000836402 (3:184160425 G>A), RS1000836813 (3:184161990 G>A), RS1001116856 (3:184169147 G>C), RS1001262295 (3:184156997 T>C), RS1001342675 (3:184171032 T>A), RS1001390194 (3:184164214 C>A), RS1001550215 (3:184163039 A>T), RS1001735599 (3:184155058 A>G,T), RS1001831535 (3:184161833 C>G), RS1001880771 (3:184161617 T>G)

Disease associations

OMIM: gene MIM:601368 | disease phenotypes: MIM:616894, MIM:616331, MIM:180700

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant Robinow syndrome 3	Definitive	Autosomal dominant
autosomal dominant Robinow syndrome	Supportive	Autosomal dominant

Mondo (4): autosomal dominant Robinow syndrome 3 (MONDO:0014819), autosomal dominant Robinow syndrome 2 (MONDO:0014591), autosomal dominant Robinow syndrome 1 (MONDO:0024455), autosomal dominant Robinow syndrome (MONDO:0008389)

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

HPO phenotypes

106 total (30 of 106 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:0000076	Vesicoureteral reflux
HP:0000168	Abnormality of the gingiva
HP:0000175	Cleft palate
HP:0000207	Triangular mouth
HP:0000212	Gingival overgrowth
HP:0000256	Macrocephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000465	Webbed neck

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001469_1	Major depressive disorder	5.000000e-06
GCST007989_7	Facial morphology traits (63 three-dimensional facial segments)	8.000000e-10
GCST90002390_302	Mean corpuscular hemoglobin	6.000000e-09
GCST90002392_723	Mean corpuscular volume	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6028 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
Air Pollutants	affects expression, increases abundance, increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression, affects methylation	2
Valproic Acid	affects expression, decreases methylation	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
methylselenic acid	increases expression	1
salinomycin	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
perfluorooctanoic acid	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
Oxaliplatin	increases expression	1
Acetaminophen	increases expression	1
Glyphosate	increases expression	1
Arsenates	affects cotreatment, increases expression	1
Atrazine	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Cannabinoids	increases abundance, affects methylation	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Niclosamide	increases expression	1
Ozone	affects expression, increases abundance	1

ChEMBL screening assays

3 unique, capped per target: 2 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1227550	Binding	Inhibition of Dvl3 overexpressed in human HEK293S assessed as inhibition of beta-casein/TCF reporter signaling at 20 uM after 18 hrs by TOPglow reporter assay	Inhibition of Wnt signaling by Dishevelled PDZ peptides. — Nat Chem Biol
CHEMBL931112	Functional	Antagonist activity at human Dvl3 assessed as inhibition of interaction between Dvl3 PDZ domain and Fz7 PDZ domain by alphaScreen assay	Indole-2-amide based biochemical antagonist of Dishevelled PDZ domain interaction down-regulates Dishevelled-driven Tcf transcriptional activity. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7X1	Abcam Raji DVL3 KO	Cancer cell line	Male
CVCL_B9XM	Abcam THP-1 DVL3 KO	Cancer cell line	Male
CVCL_C6ZH	Abcam PC-3 DVL3 KO	Cancer cell line	Male
CVCL_D7P5	Ubigene A-549 DVL3 KO	Cancer cell line	Male
CVCL_E0C9	Ubigene HeLa DVL3 KO	Cancer cell line	Female
CVCL_E1AF	Ubigene OVCAR-3 DVL3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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