FZD5

Summary

FZD5 (frizzled class receptor 5, HGNC:4043) is a protein-coding gene on chromosome 2q33.3, encoding Frizzled-5 (Q13467). Receptor for Wnt proteins.

Members of the ‘frizzled’ gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD5 protein is believed to be the receptor for the Wnt5A ligand.

Source: NCBI Gene 7855 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microphthalmia/coloboma 11 (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 137 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_003468

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4043
Approved symbol	FZD5
Name	frizzled class receptor 5
Location	2q33.3
Locus type	gene with protein product
Status	Approved
Aliases	HFZ5, DKFZP434E2135
Ensembl gene	ENSG00000163251
Ensembl biotype	protein_coding
OMIM	601723
Entrez	7855

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000295417, ENST00000908573, ENST00000937374, ENST00000937375

RefSeq mRNA: 1 — MANE Select: NM_003468 NM_003468

CCDS: CCDS33366

Canonical transcript exons

ENST00000295417 — 2 exons

Exon	Start	End
ENSE00001072750	207762598	207768994
ENSE00001072753	207769265	207769906

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 97.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.1145 / max 152.8595, expressed in 1301 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33421	3.8229	1045
33417	1.1647	511
33419	1.0203	487
33420	0.4733	251
33418	0.3754	189
33415	0.1690	87
33416	0.0546	18
33413	0.0343	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	97.82	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.55	gold quality
colonic mucosa	UBERON:0000317	97.29	gold quality
lower lobe of lung	UBERON:0008949	94.18	gold quality
ileal mucosa	UBERON:0000331	91.13	gold quality
duodenum	UBERON:0002114	90.90	gold quality
mucosa of transverse colon	UBERON:0004991	89.90	gold quality
palpebral conjunctiva	UBERON:0001812	89.54	gold quality
nephron tubule	UBERON:0001231	89.49	gold quality
eye	UBERON:0000970	88.55	gold quality
visceral pleura	UBERON:0002401	88.53	gold quality
tibia	UBERON:0000979	87.98	gold quality
trabecular bone tissue	UBERON:0002483	87.49	gold quality
liver	UBERON:0002107	87.03	gold quality
esophagus squamous epithelium	UBERON:0006920	86.74	gold quality
right lobe of liver	UBERON:0001114	86.04	gold quality
pigmented layer of retina	UBERON:0001782	85.58	gold quality
metanephric glomerulus	UBERON:0004736	85.37	gold quality
transverse colon	UBERON:0001157	85.35	gold quality
renal glomerulus	UBERON:0000074	85.33	gold quality
large intestine	UBERON:0000059	84.91	gold quality
rectum	UBERON:0001052	84.74	gold quality
colon	UBERON:0001155	84.59	gold quality
epithelium of esophagus	UBERON:0001976	83.74	gold quality
kidney epithelium	UBERON:0004819	83.71	gold quality
mucosa of paranasal sinus	UBERON:0005030	83.40	gold quality
intestine	UBERON:0000160	83.35	gold quality
jejunum	UBERON:0002115	83.30	gold quality
sigmoid colon	UBERON:0001159	82.97	gold quality
adrenal tissue	UBERON:0018303	82.09	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	569.72
E-ANND-3	yes	15.26
E-MTAB-6108	no	161.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APP, SOX4, SP1

miRNA regulators (miRDB)

210 targeting FZD5, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4455	100.00	65.48	1587
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-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-559	99.95	72.28	3609

Literature-anchored findings (GeneRIF, showing 40)

• FZD5 cells did not differ between rheumatoid arthritis and osteoarthritis (PMID:15338479)
• We found that Dkk1-Fz5, but not Dkk3-Fz5, potently synergized with LRP6 to activate signaling in a dishevelled-dependent manner. (PMID:15694380)
• 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)
• The Fz5 may be internalized through a clathrin-dependant pathway primarity when expressed in the absence of low-density lipoprotein receptor-related protein 6(LRP6). (PMID:16890161)
• POU5F1 and POU2F subfamily members play a pivotal role for the FZD5 expression in undifferentiated human ES cells, fetal liver/spleen, adult colon, pancreatic islet, and diffuse-type gastric cancer (PMID:17273778)
• Both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. Axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3. (PMID:18077588)
• These biological tools could help lead to a better understanding of Wnt-Fzd interactions and the identification of new modulators of Wnt signaling. (PMID:18230341)
• BAMBI interacts with Wnt receptor Frizzled5, coreceptor LRP6, and Dishevelled2 and increases the interaction between Frizzled5 and Dishevelled2 (PMID:18838381)
• Studies identify CVAK104 as a novel binding partner of Dishevelled (Dvl) and that CVAK104 also interacts with Fzd5. (PMID:19643732)
• Several members of the WNT pathway, including WNT5A, FZD5, and DKK1 were highly up-regulated in PCa tissue from patients with advanced PCa. (PMID:21344486)
• FZD5 was downregulated and reduced the synthesis of membrane transport protein in the hepatic membrane and the membrane stability, and accelerated the liver cell apoptosis process in alcoholic liver disease. (PMID:23337955)
• Gcm1 and Fzd5 function in an evolutionary conserved positive feedback loop that regulates trophoblast differentiation and sites of chorionic branching morphogenesis. (PMID:23610556)
• we demonstrate that innate immune functions of macrophages ensue at least partly through a homeostatic Wnt5a-Fz5-NF-kappaB (p65) circuit, which is Rac1 dependent. (PMID:24706725)
• 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)
• Wnt5a secreted by monocytes signals through the noncanonical Wnt-FZD5 pathway in mECs to induce TF expression that induces angiogenesis by autocrine regulation. (PMID:25240054)
• restoring miR-124 may function as a promising strategy to overcome P-gp-mediated MDR by inhibiting FZD5/PKC signaling. (PMID:25861751)
• Novel frameshift mutation in FZD5 in a large, extended family was identified in which non-syndromic OC segregated as an autosomal dominant disorder. Functional analysis of the mutant protein, using zebrafish, mouse retinal explants and co-culture assays, strongly suggests a dominant-negative effect on WNT signaling, which is likely responsible for optic fissure closure defects. (PMID:26908622)
• miR-224 down-regulated the Wnt/beta-catenin signaling possibly by binding to Frizzled 5 and inhibited proliferation and migration of breast cancer cells (PMID:27323393)
• FZD5 is required for the growth of RNF43-mutant pancreatic ductal adenocarcinoma cells. (PMID:27869803)
• Long non-coding RNA FTH1P3 facilitates oral squamous cell carcinoma progression by regulating miR-224-5p and FZD5. (PMID:28093311)
• KLF9 suppressed tumorigenicity of the pancreatic ductal adenocarcinoma by negatively regulating frizzled-5. (PMID:29621541)
• The current study demonstrates a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and partly does so by repression of PKC/Ets1-mediated transcription of Flt1 and Angpt2. (PMID:29845518)
• oligomerizations of FZDs and LRP5/6 can integrate the cytoplasmic protein Dishevelled into the LRP5/6 signalosome, resulting in a robust activation of ligand-independent beta-catenin signaling (PMID:30361437)
• Study shows that FZD5 exhibited a conformational change after the addition of WNT-5A, FZD5 activated Galphaq and its downstream effectors upon stimulation. (PMID:30514810)
• Results showed that mRNA expression of FZD5 was upregulated in nasal polyps and significantly higher in nasal polyp samples from patients with eosinophilic chronic rhinosinusitis (CRSwNP) than in those with non-eosinophilic CRSwNP. These findings demonstrate that FZD5 expression in nasal mucosal epithelial cells is correlated with inflammatory cells and might play a role in the pathogenesis of eosinophilic CRSwNP. (PMID:31082802)
• Confirmation of FZD5 implication in a cohort of 50 patients with ocular coloboma. (PMID:32737437)
• Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling. (PMID:32762848)
• FZD5 contributes to TNBC proliferation, DNA damage repair and stemness. (PMID:33311446)
• FZD5 regulates cellular senescence in human mesenchymal stem/stromal cells. (PMID:33338299)
• FZD5 prevents epithelial-mesenchymal transition in gastric cancer. (PMID:33618713)
• Confirming and expanding the phenotypes of FZD5 variants: Coloboma, inferior chorioretinal hypoplasia, and high myopia. (PMID:33633439)
• WNT7B represses epithelial-mesenchymal transition and stem-like properties in bladder urothelial carcinoma. (PMID:34562599)
• Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload. (PMID:34564708)
• RNF43 R117fs mutant positively regulates Wnt/beta-catenin signaling by failing to internalize FZD expressed on the cell surface. (PMID:35487932)
• Aberrant Cholesterol Metabolism and Wnt/beta-Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth. (PMID:35975457)
• Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity. (PMID:36695497)
• Single-Cell Characterization of the Frizzled 5 (Fz5) Mutant Mouse and Human Persistent Fetal Vasculature (PFV). (PMID:36867129)
• A desert lncRNA HIDEN regulates human endoderm differentiation via interacting with IMP1 and stabilizing FZD5 mRNA. (PMID:37095549)
• Insilco prediction of the role of the FriZZled5 gene in colorectal cancer. (PMID:37595345)
• Exploiting spatiotemporal regulation of FZD5 during neural patterning for efficient ventral midbrain specification. (PMID:38358799)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	fzd5	ENSDARG00000025420
mus_musculus	Fzd5	ENSMUSG00000045005
rattus_norvegicus	Fzd5	ENSRNOG00000014678
drosophila_melanogaster	fz2	FBGN0016797
drosophila_melanogaster	fz3	FBGN0027343
caenorhabditis_elegans		WBGENE00000478
caenorhabditis_elegans		WBGENE00022242

Paralogs (15): FZD3 (ENSG00000104290), SFRP1 (ENSG00000104332), SFRP4 (ENSG00000106483), FZD10 (ENSG00000111432), SFRP5 (ENSG00000120057), SMO (ENSG00000128602), SFRP2 (ENSG00000145423), FZD7 (ENSG00000155760), FZD1 (ENSG00000157240), FRZB (ENSG00000162998), FZD6 (ENSG00000164930), FZD4 (ENSG00000174804), FZD8 (ENSG00000177283), FZD2 (ENSG00000180340), FZD9 (ENSG00000188763)

Protein

Protein identifiers

Frizzled-5 — Q13467 (reviewed: Q13467)

Alternative names: FzE5

All UniProt accessions (1): Q13467

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for Wnt proteins. Functions in the canonical Wnt/beta-catenin signaling pathway. In vitro activates WNT2, WNT10B, WNT5A, but not WNT2B or WNT4 signaling. In neurons, activation by WNT7A promotes formation of synapses. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Plays a role in yolk sac angiogenesis and in placental vascularization. Plays a role in ocular development.

Subunit / interactions. Binding of unsaturated fatty acid molecules (via FZ domain) promotes homodimerization. Interacts with WNT2B. Interacts with WNT3A. Interacts with WNT7A. Interacts with GOPC.

Subcellular location. Cell membrane. Golgi apparatus membrane. Synapse. Perikaryon. Cell projection. Dendrite. Axon.

Post-translational modifications. Ubiquitinated by RNF43 and ZNRF3, leading to its degradation by the proteasome.

Disease relevance. Microphthalmia/Coloboma 11 (MCOPCB11) [MIM:620731] A form of colobomatous microphthalmia, a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like coloboma, opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). MCOPCB11 is an autosomal dominant form with incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PDZ-binding motif mediates interaction with GOPC. 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_003459* (*=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
IPR037441	FZ5_CRD	Domain

Pfam: PF01392, PF01534

UniProt features (53 total): topological domain 8, helix 8, transmembrane region 7, sequence variant 7, sequence conflict 7, disulfide bond 5, short sequence motif 2, glycosylation site 2, signal peptide 1, chain 1, domain 1, region of interest 1, compositionally biased region 1, turn 1, strand 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6O39	X-RAY DIFFRACTION	1.8
5URY	X-RAY DIFFRACTION	2.1
5URZ	X-RAY DIFFRACTION	2.2
6WW2	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13467-F1	82.67	0.56

Antibody-complex structures (SAbDab): 2 — 6O39, 6WW2

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): 33–94, 41–87, 78–116, 105–147, 109–133

Glycosylation sites (2): 47, 151

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
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-4641263	Regulation of FZD by ubiquitination
R-HSA-5140745	WNT5A-dependent internalization of FZD2, FZD5 and ROR2
R-HSA-5340588	Signaling by RNF43 mutants

MSigDB gene sets: 492 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_REGULATION_OF_AUTOPHAGY, KOBAYASHI_EGFR_SIGNALING_24HR_UP, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_AXIS_SPECIFICATION, GU_PDEF_TARGETS_DN, GOBP_SYNAPSE_ASSEMBLY, GOBP_EMBRYONIC_AXIS_SPECIFICATION, TTCCGTT_MIR191, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE

GO Biological Process (37): embryonic axis specification (GO:0000578), angiogenesis (GO:0001525), eye development (GO:0001654), glandular epithelial cell maturation (GO:0002071), positive regulation of T cell cytokine production (GO:0002726), synapse assembly (GO:0007416), negative regulation of cell population proliferation (GO:0008285), anterior/posterior axis specification, embryo (GO:0008595), neuron differentiation (GO:0030182), post-embryonic camera-type eye development (GO:0031077), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of tumor necrosis factor production (GO:0032760), T cell differentiation in thymus (GO:0033077), non-canonical Wnt signaling pathway (GO:0035567), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic camera-type eye morphogenesis (GO:0048596), Spemann organizer formation (GO:0060061), canonical Wnt signaling pathway (GO:0060070), apoptotic process involved in morphogenesis (GO:0060561), intestinal epithelial cell maturation (GO:0060574), branching involved in labyrinthine layer morphogenesis (GO:0060670), syncytiotrophoblast cell differentiation involved in labyrinthine layer development (GO:0060715), labyrinthine layer blood vessel development (GO:0060716), chorionic trophoblast cell differentiation (GO:0060718), cellular response to molecule of bacterial origin (GO:0071219), regulation of chorionic trophoblast cell proliferation (GO:1901382), regulation of mitophagy (GO:1901524), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), regulation of bicellular tight junction assembly (GO:2000810), vasculature development (GO:0001944), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), Wnt signaling pathway (GO:0016055), embryonic camera-type eye development (GO:0031076), system development (GO:0048731)

GO Molecular Function (10): amyloid-beta binding (GO:0001540), G protein-coupled receptor activity (GO:0004930), lipid binding (GO:0008289), Wnt-protein binding (GO:0017147), protein kinase binding (GO:0019901), ubiquitin protein ligase binding (GO:0031625), Wnt receptor activity (GO:0042813), protein-containing complex binding (GO:0044877), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (15): Golgi membrane (GO:0000139), plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), clathrin-coated endocytic vesicle membrane (GO:0030669), early endosome membrane (GO:0031901), perikaryon (GO:0043204), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), early endosome (GO:0005769), Golgi apparatus (GO:0005794), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-5 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
Wnt signaling pathway	3
binding	3
anatomical structure formation involved in morphogenesis	2
transmembrane signaling receptor activity	2
neuron projection	2
cytoplasm	2
axis specification	1
embryonic pattern specification	1
blood vessel morphogenesis	1
sensory organ development	1
visual system development	1
glandular epithelial cell development	1
columnar/cuboidal epithelial cell maturation	1
T cell cytokine production	1
positive regulation of T cell mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of T cell cytokine production	1
nervous system development	1
cell junction assembly	1
synapse organization	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
embryonic axis specification	1
tripartite regional subdivision	1
anterior/posterior axis specification	1
cell differentiation	1
generation of neurons	1
post-embryonic development	1
camera-type eye development	1
positive regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1

Protein interactions and networks

STRING

1367 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FZD5	WNT5A	P41221	998
FZD5	WNT7A	O00755	982
FZD5	DVL1	O14640	878
FZD5	WNT4	P56705	861
FZD5	DVL2	O14641	847
FZD5	LRP6	O75581	839
FZD5	WNT5B	Q9H1J7	800
FZD5	RORA	P35397	796
FZD5	WNT7B	P56706	795
FZD5	CTNNB1	P35222	793
FZD5	WNT3A	P56704	792
FZD5	LRP5	O75197	772
FZD5	PTH2R	P49190	769
FZD5	WNT11	O96014	758
FZD5	WNT6	Q9Y6F9	748

IntAct

29 interactions, top by confidence:

A	B	Type	Score
tcdB	FZD5	psi-mi:“MI:0407”(direct interaction)	0.610
FZD5	tcdB	psi-mi:“MI:0915”(physical association)	0.610
SLC35B1	FZD5	psi-mi:“MI:0915”(physical association)	0.560
SCYL2	FZD5	psi-mi:“MI:0915”(physical association)	0.540
FZD5	SCYL2	psi-mi:“MI:0407”(direct interaction)	0.540
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
tcdB	FZD5	psi-mi:“MI:0407”(direct interaction)	0.440
FZD5	TRABD2B	psi-mi:“MI:0403”(colocalization)	0.430
FZD5	TRABD2B	psi-mi:“MI:0914”(association)	0.430
WNT2B	FZD5	psi-mi:“MI:0915”(physical association)	0.400
FZD5	BAMBI	psi-mi:“MI:0915”(physical association)	0.400
RGS2	FZD5	psi-mi:“MI:0915”(physical association)	0.370
FZD5	ABI3BP	psi-mi:“MI:0915”(physical association)	0.370
FZD5	LZTFL1	psi-mi:“MI:0915”(physical association)	0.370
UBTD1	FZD5	psi-mi:“MI:0915”(physical association)	0.370
FZD5	GSK3B	psi-mi:“MI:0915”(physical association)	0.370
FZD5	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
LGR4	FZD7	psi-mi:“MI:0914”(association)	0.350
FZD5	FZD7	psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
FZD5	LRRK2	psi-mi:“MI:0403”(colocalization)	0.270
FZD5	WNT5A	psi-mi:“MI:2364”(proximity)	0.270
SLC35B1	FZD5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): FZD5 (Proximity Label-MS), FZD5 (Co-localization), FZD5 (Affinity Capture-Western), RNF43 (Affinity Capture-Western), DVL2 (Affinity Capture-Western), FZD5 (Affinity Capture-Western), FZD5 (Affinity Capture-MS), FZD5 (Affinity Capture-RNA), FZD5 (Two-hybrid), FZD5 (Proximity Label-MS), FZD5 (Proximity Label-MS), FZD5 (PCA), FZD5 (Affinity Capture-Western), TMEM79 (Affinity Capture-Western), USP8 (Affinity Capture-Western)

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

12 interactions.

A	Effect	B	Mechanism
WNT10B	up-regulates	FZD5	binding
BAMBI	up-regulates	FZD5	binding
FZD5	“up-regulates activity”	DVL1	binding
FZD5	“up-regulates activity”	DVL2	binding
FZD5	“up-regulates activity”	DVL3	binding
FZD5	“up-regulates activity”	LRP6	binding
FZD5	“up-regulates activity”	LRP5	binding
ZNRF3	“down-regulates quantity”	FZD5	ubiquitination
hsa-miR-124-5p	“down-regulates quantity by repression”	FZD5	“post transcriptional regulation”
WNT5A	up-regulates	FZD5	binding
FZD5	down-regulates	CEBPA
FZD5	down-regulates	PPARG

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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.

GO biological processes:

GO term	Partners	Fold	FDR
canonical Wnt signaling pathway	5	42.6×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	99
Likely benign	11
Benign	13

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
3024142	NM_003468.4(FZD5):c.656delinsAG (p.Ala219fs)	Pathogenic
3024143	NM_003468.4(FZD5):c.830del (p.Cys277fs)	Pathogenic
3024145	NM_003468.4(FZD5):c.1232A>G (p.Tyr411Cys)	Pathogenic
3024146	NM_003468.4(FZD5):c.1428del (p.Ser477fs)	Pathogenic
3024147	NM_003468.4(FZD5):c.1403_1406dup (p.Tyr470fs)	Pathogenic
3377022	NM_003468.4(FZD5):c.1146del (p.Asp382fs)	Likely pathogenic
4531810	NM_003468.4(FZD5):c.986G>T (p.Ser329Ile)	Likely pathogenic
694330	NM_003468.4(FZD5):c.1081_1082insGAA (p.His361delinsArgAsn)	Likely pathogenic
694331	NM_003468.4(FZD5):c.1181_1246del (p.Asn394_Gly415del)	Likely pathogenic

SpliceAI

233 predictions. Top by Δscore:

Variant	Effect	Δscore
2:207769259:TCTCA:T	donor_loss	0.9800
2:207769260:CTCA:C	donor_loss	0.9800
2:207769261:TCA:T	donor_loss	0.9800
2:207769262:CA:C	donor_loss	0.9800
2:207769263:A:AC	donor_gain	0.9600
2:207769263:ACCT:A	donor_gain	0.9600
2:207769264:C:CC	donor_gain	0.9600
2:207769264:CCT:C	donor_gain	0.9600
2:207769264:CCTC:C	donor_gain	0.9600
2:207769266:T:TA	donor_gain	0.9600
2:207768996:T:C	acceptor_gain	0.9400
2:207768993:CT:C	acceptor_gain	0.9300
2:207768995:C:CC	acceptor_gain	0.9300
2:207768997:T:TC	acceptor_gain	0.9200
2:207768997:T:C	acceptor_gain	0.9100
2:207766831:T:TA	donor_gain	0.9000
2:207767045:G:A	donor_gain	0.9000
2:207768990:GGACT:G	acceptor_gain	0.8900
2:207768995:C:G	acceptor_gain	0.8900
2:207768991:GACT:G	acceptor_gain	0.8800
2:207766944:C:A	donor_gain	0.8700
2:207768993:CTCTT:C	acceptor_gain	0.8700
2:207768994:TCTTT:T	acceptor_gain	0.8700
2:207766950:G:C	donor_gain	0.8400
2:207766954:T:A	donor_gain	0.8200
2:207767157:TC:T	donor_gain	0.8000
2:207767158:CC:C	donor_gain	0.8000
2:207768994:TCT:T	acceptor_loss	0.7700
2:207768995:C:A	acceptor_loss	0.7700
2:207766994:CAGGG:C	donor_gain	0.7600

AlphaMissense

3771 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:207768300:C:G	C147S	1.000
2:207768301:A:T	C147S	1.000
2:207768342:C:T	C133Y	1.000
2:207768359:C:A	W127C	1.000
2:207768359:C:G	W127C	1.000
2:207768361:A:G	W127R	1.000
2:207768361:A:T	W127R	1.000
2:207768365:G:C	F125L	1.000
2:207768365:G:T	F125L	1.000
2:207768366:A:C	F125C	1.000
2:207768366:A:G	F125S	1.000
2:207768367:A:G	F125L	1.000
2:207768392:G:C	C116W	1.000
2:207768393:C:A	C116F	1.000
2:207768393:C:G	C116S	1.000
2:207768393:C:T	C116Y	1.000
2:207768394:A:G	C116R	1.000
2:207768394:A:T	C116S	1.000
2:207768414:C:A	C109F	1.000
2:207768414:C:G	C109S	1.000
2:207768414:C:T	C109Y	1.000
2:207768415:A:G	C109R	1.000
2:207768415:A:T	C109S	1.000
2:207768425:G:C	C105W	1.000
2:207768426:C:G	C105S	1.000
2:207768426:C:T	C105Y	1.000
2:207768427:A:T	C105S	1.000
2:207768459:C:G	C94S	1.000
2:207768459:C:T	C94Y	1.000
2:207768460:A:G	C94R	1.000

dbSNP variants (sampled 300 via entrez): RS1000444908 (2:207771685 A>G), RS1000650412 (2:207767138 G>C), RS1000660229 (2:207766878 G>A,T), RS1000820641 (2:207765332 G>A,T), RS1000934893 (2:207765032 T>C), RS1001195482 (2:207766090 AAAAAAAG>A), RS1001310225 (2:207766443 G>A), RS1002867621 (2:207767609 C>A), RS1003199764 (2:207769238 G>A,T), RS1004216414 (2:207765452 C>G,T), RS1004234744 (2:207766841 C>A), RS1004330160 (2:207771232 T>C), RS1004340121 (2:207770914 G>C), RS1004888959 (2:207767888 G>A,T), RS1005272679 (2:207764382 A>G)

Disease associations

OMIM: gene MIM:601723 | disease phenotypes: MIM:600057, MIM:620731

GenCC curated gene-disease

Disease	Classification	Inheritance
microphthalmia/coloboma 11	Strong	Autosomal dominant

Mondo (3): bladder exstrophy-epispadias-cloacal exstrophy complex (MONDO:0700039), microphthalmia/coloboma 11 (MONDO:0958239), coloboma (MONDO:0001476)

Orphanet (2): Classic bladder exstrophy (Orphanet:93930), OBSOLETE: Ocular coloboma (Orphanet:194)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000480	Retinal coloboma
HP:0000486	Strabismus
HP:0000541	Retinal detachment
HP:0000567	Chorioretinal coloboma
HP:0000568	Microphthalmia
HP:0000588	Optic disc coloboma
HP:0000612	Iris coloboma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0003577	Congenital onset
HP:0007663	Reduced visual acuity
HP:0007750	Hypoplasia of the fovea
HP:0007766	Optic disc hypoplasia
HP:0008499	High hypermetropia
HP:0011003	High myopia
HP:0100019	Cortical cataract

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002383_199	Hematocrit	1.000000e-09
GCST90002384_242	Hemoglobin	4.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3559687 (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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects cotreatment, decreases expression, affects expression	9
trichostatin A	affects cotreatment, decreases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
bisphenol A	decreases expression, affects cotreatment, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Carbamazepine	affects expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
decabromobiphenyl ether	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
tetrachlorodian	increases expression	1
cordycepin	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
imeglimin	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Adenosine	increases expression	1
Allergens	affects cotreatment, increases abundance, increases expression	1

ChEMBL screening assays

8 unique, capped per target: 6 functional, 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4376174	Binding	Binding affinity to recombinant human Frizzled-5 (Ala27 to Pro167 residues)/human IgG1 chimeric protein expressed in mouse NS0 cells by SPR assay	Lead Optimization Yields High Affinity Frizzled 7-Targeting Peptides That Modulate Clostridium difficile Toxin B Pathogenicity in Epithelial Cells. — J Med Chem
CHEMBL4807089	Functional	Agonist activity at frizzled-5 (unknown origin) expressed in human HEK293superTOP flash cells by luciferase reporter gene assay	Antagonistic peptides for frizzled-1 and frizzled-2

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7QB	Ubigene A-549 FZD5 KO	Cancer cell line	Male
CVCL_SP18	HAP1 FZD5 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00368004	Not specified	TERMINATED	Family Studies of Uveal Coloboma
NCT01778543	Not specified	RECRUITING	Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC)
NCT04833361	Not specified	COMPLETED	Potential Environmental Causes of Uveal Coloboma
NCT06293560	Not specified	RECRUITING	Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children