FZD2

Summary

FZD2 (frizzled class receptor 2, HGNC:4040) is a protein-coding gene on chromosome 17q21.31, encoding Frizzled-2 (Q14332). Receptor for Wnt proteins.

This intronless gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the wingless type MMTV integration site family of signaling proteins. This gene encodes a protein that is coupled to the beta-catenin canonical signaling pathway. Competition between the wingless-type MMTV integration site family, member 3A and wingless-type MMTV integration site family, member 5A gene products for binding of this protein is thought to regulate the beta-catenin-dependent and -independent pathways.

Source: NCBI Gene 2535 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant omodysplasia (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 240 total — 3 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 110
• Druggable target: yes
• MANE Select transcript: NM_001466

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4040
Approved symbol	FZD2
Name	frizzled class receptor 2
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000180340
Ensembl biotype	protein_coding
OMIM	600667
Entrez	2535

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000315323

RefSeq mRNA: 1 — MANE Select: NM_001466 NM_001466

CCDS: CCDS11484

Canonical transcript exons

ENST00000315323 — 1 exons

Exon	Start	End
ENSE00001253937	44557484	44561262

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 93.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.6126 / max 286.7875, expressed in 1433 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161172	6.7135	925
161169	2.7547	1175
161170	2.3083	795
161171	1.4483	688
161174	1.1011	394
161175	0.5449	276
161173	0.4532	286
161176	0.1605	49
161177	0.1279	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	93.98	gold quality
embryo	UBERON:0000922	91.29	gold quality
dorsal root ganglion	UBERON:0000044	89.65	gold quality
ganglionic eminence	UBERON:0004023	88.46	gold quality
stromal cell of endometrium	CL:0002255	87.34	gold quality
trigeminal ganglion	UBERON:0001675	83.68	gold quality
renal glomerulus	UBERON:0000074	83.15	gold quality
metanephric glomerulus	UBERON:0004736	82.79	gold quality
pigmented layer of retina	UBERON:0001782	81.74	gold quality
right coronary artery	UBERON:0001625	80.23	gold quality
metanephros	UBERON:0000081	79.55	gold quality
thoracic aorta	UBERON:0001515	79.54	gold quality
ascending aorta	UBERON:0001496	79.53	gold quality
endometrium epithelium	UBERON:0004811	78.21	gold quality
descending thoracic aorta	UBERON:0002345	78.20	gold quality
monocyte	CL:0000576	76.67	gold quality
visceral pleura	UBERON:0002401	76.42	gold quality
mononuclear cell	CL:0000842	76.24	gold quality
leukocyte	CL:0000738	76.21	gold quality
saphenous vein	UBERON:0007318	75.97	gold quality
tibial nerve	UBERON:0001323	75.16	gold quality
granulocyte	CL:0000094	75.02	gold quality
cortex of kidney	UBERON:0001225	74.30	gold quality
coronary artery	UBERON:0001621	74.23	gold quality
superficial temporal artery	UBERON:0001614	74.16	silver quality
left coronary artery	UBERON:0001626	73.88	gold quality
cartilage tissue	UBERON:0002418	73.59	silver quality
aorta	UBERON:0000947	73.58	gold quality
endometrium	UBERON:0001295	72.63	gold quality
pleura	UBERON:0000977	72.41	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6911	yes	108.05
E-ANND-3	no	1.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, GATA6, HMGA2

miRNA regulators (miRDB)

98 targeting FZD2, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220

Literature-anchored findings (GeneRIF, showing 29)

• Dead ringer’s preference for AT-rich DNA originates from three positions within the ARID fold that form energetically significant contacts to an adenine-thymine base step. (PMID:11867548)
• RETN has a role in Drosophila preblastoderm syncytial mitoses (PMID:12141428)
• Data suggest that Drosphila dead ringer is an important regulator of the late development of longitudinal glia. (PMID:12620977)
• three genes, dead ringer (dri), Serrate (Ser), and trh itself, are expressed in the embryonic salivary duct independently of trh (PMID:12798300)
• retained/dead ringer is necessary for neuronal pathfinding, female receptivity and repression of fruitless independent male courtship behaviors (PMID:15576402)
• Ror2 positively modulates Wnt3a-activated canonical signaling in a lung carcinoma, H441 cell line. This activity of Ror2 is dependent on cooperative interactions with Fzd2 but not Fzd7. (PMID:18215320)
• Human Frizzled-2 does not couple to calcium-mediated signaling through Wnt-5 protein and has slowly accumulated in canonical signaling by Wnt-3 protein. (PMID:18929644)
• Wnt5a activated Rac in the beta-catenin-independent pathway, and Frizzled2 (Fz2) and Ror1 or Ror2 were required for this action. (PMID:19910923)
• altered expression of FZD2 might be associated with a proliferative status, thus playing a role in the biology of human medulloblastomas (PMID:21850537)
• Data suggest that an anti-Wnt5a antibody was capable of suppressing Wnt5a-dependent internalization of Fz2 receptor, resulting in the prevention of metastasis of gastric cancer cells by inhibiting the activation of Rac1 and the expression of laminin gamma2. (PMID:22101459)
• It is associated with poor prognosis in glioblastoma patients. (PMID:23748645)
• Pharmacologic and genetic perturbations reveal that Fzd2 drives epithelial-mesenchymal transition and cell migration through a previously unrecognized, noncanonical pathway that includes Fyn and Stat3. (PMID:25417160)
• Fz2 was positive in both the cell membrane and cytoplasm of gastric cancer tissues of moderately differentiated and poorly differentiated adenocarcinoma.Fz2 expression pattern in normal stomach tissues. (PMID:25586465)
• FZD2 was downregulated in an adenoid cystic carcinoma cell line with high metastatic potential, vs another with low potential. Knockdown of FZD2 downregulated the expression of PAI-1. (PMID:25695658)
• the FRIZZLED2 mutation is a de novo, novel cause for autosomal dominant omodysplasia. (PMID:25759469)
• CD82 enhanced the expression of miR-203 and directly downregulated FZD2 expression, suppressing cancer metastasis/cell migration by inhibiting the Wnt signaling pathway. (PMID:26132195)
• the present study demonstrated that Fzd2 contributes to the migration and invasion of OSCC cells, at least partly through regulation of the STAT3 pathway (PMID:26398330)
• Sonazoid enhanced sonoporation of the cells with the diagnostic US device and the suppression of proliferation of both HCC cell lines by shRNA-Fz2. (PMID:26648389)
• our study suggests a role for FZD2 in high-risk neuroblastoma cell growth (PMID:27323822)
• Fzd2 did not influence the proliferation of EC cells. (PMID:27373314)
• Treatment of the cell lines with Fzd2 siRNA resulted in significantly reduced migration and invasiveness but did not affect proliferation.Patients with high Fzd2 expression had significantly poorer recurrencefree survival than those with low expression (PMID:28350091)
• Down-regulation of miR-30a-3p/5p promotes esophageal squamous cell carcinoma cell proliferation by activating the Wnt signaling pathway through inhibition of Wnt2 and Fzd2. (PMID:29259372)
• The results indicate that OMOD2 or Robinow syndome-like phenotype can be caused by a heterozygous nonsense FZD2 mutation impairing Wnt signaling. (PMID:29383834)
• this study presents the crystal structure of a TcdB fragment in complex with the cysteine-rich domain of human FZD2 at 2.5-angstrom resolution, which reveals an endogenous FZD-bound fatty acid acting as a co-receptor for TcdB binding. (PMID:29748286)
• FZD2 could promote clinically relevant EMT, CD44(+) stem-like properties, and the VM phenotype in HCC involving a potential Hippo signaling pathway-dependent mechanism, and should be considered as a promising therapeutic target for the treatment of HCC. (PMID:30677195)
• Fz2 and Wnt5a, might be involved in human Amyotrophic lateral sclerosis pathology. (PMID:30924074)
• FZD2 acts as an oncogene in tongue cancer, promoting cell growth, invasion and migration. (PMID:31595151)
• Integrated weighted gene coexpression network analysis identifies Frizzled 2 (FZD2) as a key gene in invasive malignant pleomorphic adenoma. (PMID:34986855)
• Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome. (PMID:38967226)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fzd2	ENSDARG00000054438
mus_musculus	Fzd2	ENSMUSG00000050288
rattus_norvegicus	Fzd2	ENSRNOG00000021962
drosophila_melanogaster	fz3	FBGN0027343

Paralogs (15): FZD3 (ENSG00000104290), SFRP1 (ENSG00000104332), SFRP4 (ENSG00000106483), FZD10 (ENSG00000111432), SFRP5 (ENSG00000120057), SMO (ENSG00000128602), SFRP2 (ENSG00000145423), FZD7 (ENSG00000155760), FZD1 (ENSG00000157240), FRZB (ENSG00000162998), FZD5 (ENSG00000163251), FZD6 (ENSG00000164930), FZD4 (ENSG00000174804), FZD8 (ENSG00000177283), FZD9 (ENSG00000188763)

Protein

Protein identifiers

Frizzled-2 — Q14332 (reviewed: Q14332)

Alternative names: FzE2

All UniProt accessions (1): Q14332

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. (Microbial infection) Acts as a receptor for C.difficile toxin TcdB in the colonic epithelium. TcdB occupies the binding site for Wnt-adducted palmitoleate in frizzled receptors and TcdB-binding prevents Wnt-binding and downstream Wnt signaling.

Subunit / interactions. (Microbial infection) Interacts with C.difficile toxin TcdB; frizzled receptors constitute the major host receptors for TcdB in the colonic epithelium.

Subcellular location. Membrane. Cell membrane.

Tissue specificity. Widely expressed. In the adult, mainly found in heart, placenta, skeletal muscle, lung, kidney, pancreas, prostate, testis, ovary and colon. In the fetus, expressed in brain, lung and kidney. Low levels in fetal liver.

Post-translational modifications. Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.

Disease relevance. Omodysplasia 2 (OMOD2) [MIM:164745] A rare autosomal dominant skeletal dysplasia characterized by short humeri, radial head dislocation, short first metacarpals, facial dysmorphism and genitourinary anomalies. The disease is caused by variants affecting the gene represented in this entry. Defects in FZD2 have been found in patients with Robinow syndrome-like features including short-limb dwarfism, broad thumbs and craniofacial abnormalities.

Domain organisation. Lys-Thr-X-X-X-Trp motif interacts with the PDZ domain of Dvl (Disheveled) family members and is involved in the activation of the Wnt/beta-catenin signaling pathway. The FZ domain is involved in binding with Wnt ligands.

Similarity. Belongs to the G-protein coupled receptor Fz/Smo family.

RefSeq proteins (1): NP_001457* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000539	Frizzled/Smoothened_7TM	Domain
IPR015526	Frizzled/SFRP	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR020067	Frizzled_dom	Domain
IPR036790	Frizzled_dom_sf	Homologous_superfamily
IPR041778	FZ2_CRD	Domain

Pfam: PF01392, PF01534

UniProt features (49 total): topological domain 8, helix 8, transmembrane region 7, sequence variant 6, disulfide bond 5, strand 4, short sequence motif 2, glycosylation site 2, mutagenesis site 2, signal peptide 1, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7X8P	X-RAY DIFFRACTION	2.24
6C0B	X-RAY DIFFRACTION	2.5
7N95	ELECTRON MICROSCOPY	4.1
7N97	ELECTRON MICROSCOPY	5.1
7N9S	ELECTRON MICROSCOPY	5.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14332-F1	84.33	0.61

Antibody-complex structures (SAbDab): 1 — 7X8P

Functional residue map

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

Disulfide bonds (5): 39–100, 47–93, 84–121, 110–150, 114–138

Glycosylation sites (2): 53, 154

Mutagenesis-validated functional residues (2):

Position	Phenotype
77	strongly reduced interaction with c.difficile toxin tcdb.
127	strongly reduced interaction with c.difficile toxin tcdb.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-4086398	Ca2+ pathway
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane
R-HSA-5140745	WNT5A-dependent internalization of FZD2, FZD5 and ROR2

MSigDB gene sets: 575 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, SP3_Q3, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_NEUROGENESIS, SP1_Q2_01

GO Biological Process (19): membranous septum morphogenesis (GO:0003149), muscular septum morphogenesis (GO:0003150), outflow tract morphogenesis (GO:0003151), cell-cell signaling (GO:0007267), sensory perception of smell (GO:0007608), Wnt signaling pathway (GO:0016055), neuron differentiation (GO:0030182), non-canonical Wnt signaling pathway (GO:0035567), endothelial cell differentiation (GO:0045446), positive regulation of DNA-templated transcription (GO:0045893), hard palate development (GO:0060022), canonical Wnt signaling pathway (GO:0060070), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), inner ear receptor cell development (GO:0060119), cochlea morphogenesis (GO:0090103), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), ventricular septum morphogenesis (GO:0060412)

GO Molecular Function (6): G protein-coupled receptor activity (GO:0004930), Wnt-protein binding (GO:0017147), PDZ domain binding (GO:0030165), Wnt receptor activity (GO:0042813), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), focal adhesion (GO:0005925), clathrin-coated endocytic vesicle membrane (GO:0030669), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
PCP/CE pathway	2
Signaling by WNT	1
GPCR ligand binding	1
Beta-catenin independent WNT signaling	1
TCF dependent signaling in response to WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Wnt signaling pathway	3
anatomical structure morphogenesis	2
ventricular septum morphogenesis	2
cell communication	2
signaling	2
signal transduction	2
transmembrane signaling receptor activity	2
cellular anatomical structure	2
muscle tissue morphogenesis	1
heart morphogenesis	1
sensory perception of chemical stimulus	1
cell surface receptor signaling pathway	1
cell differentiation	1
generation of neurons	1
endothelium development	1
epithelial cell differentiation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
anatomical structure development	1
secondary palate development	1
non-canonical Wnt signaling pathway	1
neuron development	1
inner ear receptor cell differentiation	1
inner ear morphogenesis	1
embryonic morphogenesis	1
cochlea development	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
ventricular septum development	1
cardiac septum morphogenesis	1
G protein-coupled receptor signaling pathway	1
protein binding	1
protein domain specific binding	1
Wnt-protein binding	1
signaling receptor activity	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1466 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FZD2	WNT5A	P41221	997
FZD2	WNT3A	P56704	981
FZD2	WNT4	P56705	914
FZD2	RORA	P35397	886
FZD2	CTNNB1	P35222	871
FZD2	WNT6	Q9Y6F9	864
FZD2	DVL2	O14641	861
FZD2	WNT5B	Q9H1J7	852
FZD2	WNT7B	P56706	837
FZD2	WNT2	P09544	834
FZD2	SFRP1	Q8N474	825
FZD2	WNT11	O96014	813
FZD2	WNT7A	O00755	803
FZD2	DVL1	O14640	803
FZD2	WNT1	P04628	789

IntAct

202 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
VMA12	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
tcdB	FZD2	psi-mi:“MI:0407”(direct interaction)	0.620
FZD2	tcdB	psi-mi:“MI:0407”(direct interaction)	0.620
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
LYPD6	PLXNB2	psi-mi:“MI:0914”(association)	0.530
TMPRSS12	FZD6	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
GABRE	FZD6	psi-mi:“MI:0914”(association)	0.530
P2RY1	SLC19A2	psi-mi:“MI:0914”(association)	0.530
LAMP1	FZD7	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
STS	GJA1	psi-mi:“MI:0914”(association)	0.530
NRN1	SLC1A1	psi-mi:“MI:0914”(association)	0.530
Fyn	FZD2	psi-mi:“MI:0407”(direct interaction)	0.520
FZD2	WNT3A	psi-mi:“MI:0407”(direct interaction)	0.440
tcdB	FZD2	psi-mi:“MI:0407”(direct interaction)	0.440
FZD2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
FZD2	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI3	FZD2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (96): FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS)

ESM2 similar proteins: B3DIG4, O00144, O57328, O57329, O70421, O75084, O93274, P18537, P23385, P27115, P27808, P41594, P55013, P58421, P97772, Q08463, Q08464, Q13255, Q13467, Q14332, Q24760, Q498S8, Q5BL72, Q5RH73, Q61090, Q61091, Q6NVG7, Q6P9A2, Q6PA90, Q8AVJ9, Q8BKG4, Q8CHL0, Q8IYK4, Q8K4C8, Q9DEB5, Q9EQD0, Q9H461, Q9I9M5, Q9IA02, Q9IA06

Diamond homologs: A0A0K3AWM6, B3DIG4, G5ECQ2, O00144, O19116, O42579, O57328, O57329, O60353, O70421, O75084, O93274, P18537, P58421, P97299, P97401, Q08463, Q08464, Q13467, Q14332, Q24760, Q498S8, Q5BL72, Q5RCN4, Q5RF67, Q5T4F7, Q61086, Q61088, Q61089, Q61090, Q61091, Q6FHJ7, Q7YRN1, Q80YN4, Q863H1, Q8AVJ9, Q8BKG4, Q8C4U3, Q8CHL0, Q8K4C8

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
WNT3A	up-regulates	FZD2	binding
WNT5A	down-regulates	FZD2	binding
ZNRF3	“down-regulates quantity by destabilization”	FZD2	ubiquitination
ZNRF3	down-regulates	FZD2	ubiquitination
RNF43	up-regulates	FZD2	relocalization
ZNRF3	down-regulates	FZD2	relocalization
WNT5A	“up-regulates activity”	FZD2	binding
FZD2	“up-regulates activity”	DVL1	binding
FZD2	“up-regulates activity”	DVL2	binding
FZD2	“up-regulates activity”	DVL3	binding
FZD2	“up-regulates activity”	LRP6	binding
FZD2	“up-regulates activity”	LRP5	binding
FZD2	down-regulates	CEBPA
FZD2	down-regulates	PPARG
WNT10B	up-regulates	FZD2	binding
FZD2	“up-regulates activity”	SETDB1/NLK/CHD7

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 175 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
Ras activation upon Ca2+ influx through NMDA receptor	5	26.9×	1e-04
Unblocking of NMDA receptors, glutamate binding and activation	5	25.6×	1e-04
Negative regulation of NMDA receptor-mediated neuronal transmission	5	25.6×	1e-04
Long-term potentiation	5	22.4×	2e-04
Assembly and cell surface presentation of NMDA receptors	7	16.8×	4e-05
Neurexins and neuroligins	8	14.9×	2e-05
RHOJ GTPase cycle	5	9.4×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	33.3×	4e-09
protein localization to synapse	6	29.3×	1e-05
receptor clustering	7	27.8×	2e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	7	22.1×	8e-06
maintenance of blood-brain barrier	5	15.3×	1e-03
monoatomic ion transmembrane transport	6	8.0×	7e-03
cell-cell adhesion	10	6.5×	5e-04
protein localization to plasma membrane	8	5.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	5
Uncertain significance	163
Likely benign	45
Benign	16

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
3384022	NM_001466.4(FZD2):c.254C>A (p.Ser85Ter)	Pathogenic
617609	NM_001466.4(FZD2):c.1644G>A (p.Trp548Ter)	Pathogenic
981470	NM_001466.4(FZD2):c.367_388dup (p.Phe130fs)	Pathogenic
1012421	NM_001466.4(FZD2):c.1301G>C (p.Gly434Ala)	Likely pathogenic
2910434	NM_001466.4(FZD2):c.1640C>A (p.Ser547Ter)	Likely pathogenic
488052	NM_001466.4(FZD2):c.1301_1302delinsTT (p.Gly434Val)	Likely pathogenic
488061	NM_001466.4(FZD2):c.1300G>A (p.Gly434Ser)	Likely pathogenic
599512	NM_001466.4(FZD2):c.1403T>G (p.Leu468Arg)	Likely pathogenic

SpliceAI

36 predictions. Top by Δscore:

Variant	Effect	Δscore
17:44557614:G:T	donor_gain	0.6800
17:44557603:G:GT	donor_gain	0.6300
17:44557614:G:GT	donor_gain	0.6300
17:44558160:G:GT	donor_gain	0.4900
17:44557934:GC:G	donor_gain	0.4800
17:44558378:C:CT	acceptor_gain	0.4600
17:44557497:C:T	donor_gain	0.4400
17:44557617:G:GT	donor_gain	0.4100
17:44557907:GCACC:G	donor_gain	0.3900
17:44558324:C:G	donor_gain	0.3800
17:44558308:TGCC:T	donor_gain	0.3600
17:44558310:C:CG	donor_gain	0.3100
17:44557972:T:G	donor_gain	0.3000
17:44557561:TA:T	donor_gain	0.2800
17:44557562:AA:A	donor_gain	0.2800
17:44557563:AA:A	donor_gain	0.2800
17:44557560:G:GG	donor_gain	0.2700
17:44557559:A:AG	donor_gain	0.2600
17:44557929:AAG:A	donor_gain	0.2600
17:44558309:G:A	donor_gain	0.2400
17:44558397:TCACA:T	acceptor_loss	0.2400
17:44558398:CACA:C	acceptor_loss	0.2400
17:44558399:ACAGG:A	acceptor_loss	0.2400
17:44558400:CAGGA:C	acceptor_loss	0.2400
17:44558401:AG:A	acceptor_loss	0.2400
17:44558402:G:GC	acceptor_loss	0.2400
17:44558400:CAGG:C	acceptor_gain	0.2300
17:44558401:AGGA:A	acceptor_gain	0.2300
17:44558402:GGAG:G	acceptor_gain	0.2300
17:44558311:C:CT	donor_gain	0.2200

AlphaMissense

3676 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:44557803:T:A	C39S	1.000
17:44557803:T:C	C39R	1.000
17:44557804:G:A	C39Y	1.000
17:44557804:G:C	C39S	1.000
17:44557813:T:A	I42N	1.000
17:44557827:T:A	C47S	1.000
17:44557827:T:C	C47R	1.000
17:44557827:T:G	C47G	1.000
17:44557828:G:A	C47Y	1.000
17:44557828:G:C	C47S	1.000
17:44557828:G:T	C47F	1.000
17:44557829:C:G	C47W	1.000
17:44557842:T:A	Y52N	1.000
17:44557842:T:C	Y52H	1.000
17:44557842:T:G	Y52D	1.000
17:44557843:A:G	Y52C	1.000
17:44557852:C:T	T55I	1.000
17:44557860:C:T	P58S	1.000
17:44557861:C:A	P58H	1.000
17:44557865:C:A	N59K	1.000
17:44557865:C:G	N59K	1.000
17:44557886:G:C	Q66H	1.000
17:44557886:G:T	Q66H	1.000
17:44557893:G:C	A69P	1.000
17:44557908:C:G	H74D	1.000
17:44557914:T:A	F76I	1.000
17:44557914:T:C	F76L	1.000
17:44557914:T:G	F76V	1.000
17:44557915:T:C	F76S	1.000
17:44557915:T:G	F76C	1.000

dbSNP variants (sampled 300 via entrez): RS1000123983 (17:44556492 T>G), RS1000385324 (17:44559801 T>C), RS1000641465 (17:44559968 T>C), RS1001225237 (17:44555962 G>A), RS1002070862 (17:44561331 C>T), RS1002716367 (17:44561637 A>G), RS1003325477 (17:44557548 C>T), RS1003767332 (17:44557260 G>A,C,T), RS1004523742 (17:44560128 T>C), RS1005220591 (17:44555670 G>A), RS1005294685 (17:44556950 G>A), RS1005899385 (17:44558920 C>G,T), RS1006227093 (17:44558337 G>A), RS1006874508 (17:44560089 G>T), RS1007114985 (17:44560450 A>T)

Disease associations

OMIM: gene MIM:600667 | disease phenotypes: MIM:164745, MIM:616894, MIM:616331, MIM:180700, MIM:148300

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant omodysplasia	Strong	Autosomal dominant
autosomal dominant Robinow syndrome	Supportive	Autosomal dominant

Mondo (6): autosomal dominant omodysplasia (MONDO:0008123), autosomal dominant Robinow syndrome 3 (MONDO:0014819), autosomal dominant Robinow syndrome 2 (MONDO:0014591), autosomal dominant Robinow syndrome 1 (MONDO:0024455), keratoconus (MONDO:0015486), autosomal dominant Robinow syndrome (MONDO:0008389)

Orphanet (6): Omodysplasia (Orphanet:2733), Autosomal dominant omodysplasia (Orphanet:93328), Autosomal dominant Robinow syndrome (Orphanet:3107), Robinow syndrome (Orphanet:97360), OBSOLETE: Keratoconus (Orphanet:156071), NON RARE IN EUROPE: Isolated keratoconus (Orphanet:2335)

HPO phenotypes

110 total (30 of 110 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:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000062	Ambiguous genitalia
HP:0000064	Hypoplastic labia minora
HP:0000066	Labial hypoplasia
HP:0000168	Abnormality of the gingiva
HP:0000175	Cleft palate
HP:0000212	Gingival overgrowth
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000396	Overfolded helix
HP:0000403	Recurrent otitis media
HP:0000431	Wide nasal bridge

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006629_10	Pulse pressure	4.000000e-18
GCST010703_292	Brain morphology (MOSTest)	1.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007640	Keratoconus	C11.204.627
C567664	Omodysplasia 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3559686 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Class Frizzled GPCRs

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

Ligand	Action	Affinity	Parameter
vantictumab	Antagonist	8.96	pIC50

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL4849630
7.70	EC50	20	nM	CHEMBL4847020

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases expression, affects reaction	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	decreases expression, affects cotreatment	2
Dexamethasone	affects cotreatment, increases expression, decreases expression	2
Estradiol	affects expression, decreases expression	2
Niclosamide	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression, affects cotreatment	1
methylmercuric chloride	decreases expression	1
lead acetate	decreases expression	1
salinomycin	decreases expression	1
cinnamaldehyde	increases expression	1
beta-lapachone	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
avobenzone	increases expression	1
polyhexamethyleneguanidine	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
vanillin	decreases expression	1

ChEMBL screening assays

18 unique, capped per target: 18 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4807083	Functional	Antagonist activity at Wnt3a-stimulated frizzled-2 (unknown origin) expressed in human HEK293superTOP flash cells incubated for 24 hrs by luciferase reporter gene assay	Antagonistic peptides for frizzled-1 and frizzled-2

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1SH	Abcam HeLa FZD2 KO	Cancer cell line	Female
CVCL_D7Q8	Ubigene A-549 FZD2 KO	Cancer cell line	Male
CVCL_D8LM	Ubigene HCT 116 FZD2 KO	Cancer cell line	Male
CVCL_D9F6	Ubigene HEK293 FZD2 KO	Transformed cell line	Female
CVCL_E0DG	Ubigene HeLa FZD2 KO	Cancer cell line	Female
CVCL_SP12	HAP1 FZD2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01485211	PHASE4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	PHASE4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	PHASE4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	PHASE4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	PHASE4	COMPLETED	Corneal Crosslinking Treatment Study
NCT07474870	PHASE4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT00371202	PHASE3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00647699	PHASE3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00815256	PHASE3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00887900	PHASE3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01112072	PHASE3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT01152541	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Progressive Keratoconus and Ectasia Using Riboflavin/Dextran and Hypotonic Riboflavin
NCT01190306	PHASE3	TERMINATED	Safety Study of the VEGA UV-A System to Treat Keratoconus
NCT01344187	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01459679	PHASE3	TERMINATED	Safety & Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery
NCT01464268	PHASE3	UNKNOWN	Transepithelial Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia
NCT01604135	PHASE3	ACTIVE_NOT_RECRUITING	Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial
NCT01643226	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01672814	PHASE3	COMPLETED	Microwave Treatment and Corneal Collagen Crosslinking for Keratoconus
NCT01682993	PHASE3	TERMINATED	Corneal Cross Linking and Topography Guided Excimer Laser Treatment
NCT01972854	PHASE3	TERMINATED	Safety and Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT02613780	PHASE3	UNKNOWN	Refractive Treatment of Early Keratoconus
NCT02638376	PHASE3	UNKNOWN	Evaluating the Safety and Efficacy of the KXL System for Corneal Collagen Cross-Linking in Eyes Having Keratoconus
NCT03080077	PHASE3	UNKNOWN	Safety and Effectiveness of Corneal Crosslinking (CXL): Keratoconus and Post-Refractive Ectasia
NCT03187912	PHASE3	COMPLETED	Accelerated Corneal Cross-linking With Different Riboflavin Solutions
NCT03442751	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus
NCT03858036	PHASE3	UNKNOWN	Corneal Collagen Cross-Linking (CXL) Performed With Epi-ON Versus Epi-OFF in Eyes With Keratoconus and Other Corneal Ectatic Disorders
NCT04897503	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Riboflavin/Dextran or Riboflavin/Methylcellulose
NCT04905108	PHASE3	UNKNOWN	Transepithelial (Epi-on) Corneal Collagen Crosslinking to Treat Keratoconus and Corneal Ectasia
NCT05027295	PHASE3	UNKNOWN	Accelerated Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Pulse or Continuous UV-A Light
NCT06100939	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age With Keratoconus
NCT06100952	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age with Keratoconus
NCT06450470	PHASE3	RECRUITING	Use of a Freeze-dried Amniotic Membrane Post Crosslinking in Subjects With Progressive Keratoconus
NCT06601101	PHASE3	RECRUITING	Effects of Topical Insulin on Corneal Epithelium Healing After Corneal Crosslinking in Patients With Keratoconus
NCT07124910	PHASE3	RECRUITING	Comparison of Epi-ON Corneal Collagen Crosslinking Performed Using an 18-Minute UVA Exposure vs. a 24-Minute UVA Exposure on Eyes With Ectatic Corneal Diseases
NCT07135167	PHASE3	RECRUITING	Compassionate Use Study of Epi-ON Corneal Collagen Crosslinking Performed Using UVA Exposure on Eyes With Ectatic Corneal Diseases for Subjects With Down Syndrome
NCT00409955	PHASE2	COMPLETED	Lamellar Transplant With Lyophilized Corneas
NCT00925327	PHASE2	UNKNOWN	Safety and Effectiveness of the UV-X System for Corneal Collagen Cross-Linking for Compassionate Treatment in Pediatric Patients With Progressive Keratoconus
NCT01143389	PHASE2	COMPLETED	Corneal Crosslinking in Patients With Keratoconus and Post-Refractive Ectasia
NCT01181219	PHASE2	COMPLETED	Transepithelial Corneal Collagen Cross-linking (CXL) in Treatment of Keratoconus