FZD8

Summary

FZD8 (frizzled class receptor 8, HGNC:4046) is a protein-coding gene on chromosome 10p11.21, encoding Frizzled-8 (Q9H461). 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. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. This gene is highly expressed in two human cancer cell lines, indicating that it may play a role in several types of cancer. The crystal structure of the extracellular cysteine-rich domain of a similar mouse protein has been determined.

Source: NCBI Gene 8325 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 85 total
• Druggable target: yes
• MANE Select transcript: NM_031866

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4046
Approved symbol	FZD8
Name	frizzled class receptor 8
Location	10p11.21
Locus type	gene with protein product
Status	Approved
Aliases	FZ-8
Ensembl gene	ENSG00000177283
Ensembl biotype	protein_coding
OMIM	606146
Entrez	8325

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000374694

RefSeq mRNA: 1 — MANE Select: NM_031866 NM_031866

CCDS: CCDS7192

Canonical transcript exons

ENST00000374694 — 1 exons

Exon	Start	End
ENSE00001464367	35638247	35642296

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 98.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.9312 / max 136.8508, expressed in 1332 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109111	4.4204	1189
109110	0.6221	373
109108	0.6120	379
109109	0.2768	145

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.63	gold quality
cartilage tissue	UBERON:0002418	93.83	gold quality
ganglionic eminence	UBERON:0004023	92.46	gold quality
pigmented layer of retina	UBERON:0001782	92.25	gold quality
tendon of biceps brachii	UBERON:0008188	91.97	gold quality
trabecular bone tissue	UBERON:0002483	89.89	gold quality
left ventricle myocardium	UBERON:0006566	88.71	gold quality
mammary duct	UBERON:0001765	88.45	gold quality
epithelium of mammary gland	UBERON:0003244	87.82	gold quality
epithelial cell of pancreas	CL:0000083	86.76	gold quality
pancreatic ductal cell	CL:0002079	85.93	silver quality
dorsal root ganglion	UBERON:0000044	84.49	gold quality
trigeminal ganglion	UBERON:0001675	84.05	gold quality
pericardium	UBERON:0002407	83.39	gold quality
heart right ventricle	UBERON:0002080	83.01	gold quality
renal medulla	UBERON:0000362	82.83	gold quality
sural nerve	UBERON:0015488	82.46	gold quality
tendon	UBERON:0000043	82.24	gold quality
saphenous vein	UBERON:0007318	81.12	gold quality
mammary gland	UBERON:0001911	80.79	gold quality
germinal epithelium of ovary	UBERON:0001304	80.67	gold quality
thoracic mammary gland	UBERON:0005200	80.63	gold quality
cardia of stomach	UBERON:0001162	80.44	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	80.28	silver quality
cardiac atrium	UBERON:0002081	79.97	gold quality
tibia	UBERON:0000979	79.77	gold quality
lower lobe of lung	UBERON:0008949	79.33	gold quality
calcaneal tendon	UBERON:0003701	79.27	gold quality
right atrium auricular region	UBERON:0006631	79.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELK1, PAX4

miRNA regulators (miRDB)

94 targeting FZD8, 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-190A-3P	100.00	80.35	5520
HSA-MIR-9-5P	100.00	72.28	2361
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-5193	100.00	67.26	1744
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-3617-5P	99.75	69.41	1968

Literature-anchored findings (GeneRIF, showing 20)

• molecular model of the Wnt protein binding site on the surface of dimeric CRD domain of the Fzd8 receptor (PMID:18505162)
• analysis of the frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6 (PMID:20093360)
• These observations suggest that c-Jun is involved in APF-mediated inhibition for bladder tumor cell growth (PMID:21872498)
• Soluble FZC18 and Wnt3a physically interact in a cell-free system and soluble FZC18 binds the frizzled 1 and 8 receptors. (PMID:22303445)
• APF has been shown to be a nine-residue frizzled-8 protein-related sialoglycopeptide. Subsequent research has gradually clarified the molecular mechanisms underlying the profound antiproliferative effect of APF. (PMID:22738385)
• We demonstrated an activation of Wnt-2 signaling via the Frizzled-8 receptor in non-small cell lung cancer cells (PMID:23815780)
• c-Met upregulated FZD8 through the ERK/c-Fos cascade in HN-CSC. Taken together, our results offer a preclinical proof-of-concept for targeting the c-Met/FZD8 signaling axis as a CSC-directed therapy to improve HNSCC treatment (PMID:25320014)
• report the discovery of a human-accelerated regulatory enhancer (HARE5) of FZD8, a receptor of the Wnt pathway implicated in brain development and size (PMID:25702574)
• these findings suggest that miR-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/b-catenin signaling pathway and manipulation of miR-100 may provide a promoting therapeutic strategy for cancer breast treatment. (PMID:26537584)
• Study concludes that expression of Fzd8 is repressed in multiple cancers and suggest it may have a role as a tumor suppressor. (PMID:26590425)
• Frizzled-8 has an important pro-inflammatory role and suggest that its expression is related to chronic bronchitis. (PMID:26797711)
• miR-375 functions as a tumor-suppressive microRNA by directly acting upon FZD8, which may serve as a new therapeutic target to inhibit tumor metastasis in colorectal cancer (PMID:27276676)
• Elevated expression of TP53 target FZD8 promoted prostate cancer bone metastasis by activating the canonical Wnt/beta-catenin signaling pathway. (PMID:28602974)
• FZD8 forms a TGF-beta-regulated complex with TGF-beta receptors that is mediated by the extracellular domains of FZD8 and TGFBR1 (PMID:29717114)
• Expression of FZD8 is directly correlated with ERG expression in prostate cancer. Furthermore, we show that ERG directly targets and activates FZD8 by binding to its promoter. This activation is specific to ETS transcription factor ERG and not ETV1. (PMID:30051493)
• Frizzled-4 is required for normal bone acquisition despite compensation by Frizzled-8. (PMID:31985040)
• FZD8 Indicates a Poor Prognosis and Promotes Gastric Cancer Invasion and Metastasis via B-Catenin Signaling Pathway. (PMID:32161008)
• MiR-99a alleviates apoptosis and extracellular matrix degradation in experimentally induced spine osteoarthritis by targeting FZD8. (PMID:36127685)
• Overexpressions of RHOA, CSNK1A1, DVL2, FZD8, and LRP5 genes enhance gastric cancer development in the presence of Helicobacter pylori. (PMID:36720664)
• CircMCTP2 enhances the progression of bladder cancer by regulating the miR-99a-5p/FZD8 axis. (PMID:38494582)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fzd8b	ENSDARG00000038569
danio_rerio	fzd8a	ENSDARG00000045444
mus_musculus	Fzd8	ENSMUSG00000036904
rattus_norvegicus	Fzd8	ENSRNOG00000069521
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), FZD2 (ENSG00000180340), FZD9 (ENSG00000188763)

Protein

Protein identifiers

Frizzled-8 — Q9H461 (reviewed: Q9H461)

All UniProt accessions (1): Q9H461

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes. The beta-catenin canonical signaling pathway 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. Coreceptor along with RYK of Wnt proteins, such as WNT1.

Subunit / interactions. Component of a Wnt-signaling complex that contains a WNT protein, a FZD protein and LRP5 or LRP6. Interacts directly with LRP5 or LRP6; the interaction is promoted by Wnt-binding and signaling and inhibited by DKK1. Interacts with GPOC, RSPO1 and RSPO3. Interacts with glypican GPC3.

Subcellular location. Membrane. Golgi apparatus. Cell membrane.

Tissue specificity. Most abundant in fetal kidney, followed by brain and lung. In adult tissues, expressed in kidney, heart, pancreas and skeletal muscle.

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

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_114072* (*=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
IPR041776	FZ8_CRD	Domain

Pfam: PF01392, PF01534

UniProt features (48 total): topological domain 8, transmembrane region 7, helix 6, disulfide bond 5, strand 5, region of interest 4, compositionally biased region 4, glycosylation site 3, short sequence motif 2, signal peptide 1, chain 1, domain 1, binding site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6NDZ	X-RAY DIFFRACTION	2.26
8X0T	X-RAY DIFFRACTION	2.5
21KR	ELECTRON MICROSCOPY	2.9
5UN5	X-RAY DIFFRACTION	2.99
21KS	ELECTRON MICROSCOPY	3.01
5UN6	X-RAY DIFFRACTION	3.2
21KT	ELECTRON MICROSCOPY	3.33

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H461-F1	77.05	0.43

Antibody-complex structures (SAbDab): 1 — 8X0T

Functional residue map

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

Ligand- & substrate-binding residues (1): 71–78

Disulfide bonds (5): 35–96, 43–89, 80–118, 107–148, 111–135

Glycosylation sites (3): 49, 152, 475

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-4641263	Regulation of FZD by ubiquitination
R-HSA-5340588	Signaling by RNF43 mutants

MSigDB gene sets: 181 (showing top): LI_CISPLATIN_RESISTANCE_DN, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, GOCC_SECRETORY_GRANULE, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, YY1_Q6, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, KEGG_PATHWAYS_IN_CANCER, YY1_02, GTGTTGA_MIR505, GOBP_BLOOD_VESSEL_MORPHOGENESIS, JECHLINGER_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN, GOMF_SIGNALING_RECEPTOR_BINDING, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS

GO Biological Process (9): angiogenesis (GO:0001525), neuron differentiation (GO:0030182), T cell differentiation in thymus (GO:0033077), non-canonical Wnt signaling pathway (GO:0035567), canonical Wnt signaling pathway (GO:0060070), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), Wnt signaling pathway (GO:0016055)

GO Molecular Function (8): G protein-coupled receptor activity (GO:0004930), signaling receptor binding (GO:0005102), Wnt-protein binding (GO:0017147), PDZ domain binding (GO:0030165), ubiquitin protein ligase binding (GO:0031625), Wnt receptor activity (GO:0042813), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (5): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), neuronal dense core vesicle (GO:0098992), Wnt-Frizzled-LRP5/6 complex (GO:1990851)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Wnt signaling pathway	3
signal transduction	2
transmembrane signaling receptor activity	2
protein binding	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell differentiation	1
generation of neurons	1
T cell differentiation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
cell surface receptor signaling pathway	1
G protein-coupled receptor signaling pathway	1
protein domain specific binding	1
ubiquitin-like protein ligase binding	1
Wnt-protein binding	1
signaling receptor activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cellular anatomical structure	1
dense core granule	1
plasma membrane protein complex	1

Protein interactions and networks

STRING

1185 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FZD8	WNT3A	P56704	954
FZD8	LRP6	O75581	947
FZD8	WNT3	P56703	937
FZD8	WNT11	O96014	929
FZD8	WNT1	P04628	923
FZD8	WNT2	P09544	873
FZD8	WNT5B	Q9H1J7	863
FZD8	WNT4	P56705	858
FZD8	WNT5A	P41221	846
FZD8	WNT2B	Q93097	841
FZD8	IGFBP4	P22692	831
FZD8	LRP5	O75197	818
FZD8	DVL2	O14641	802
FZD8	CTNNB1	P35222	793
FZD8	DKK4	Q9UBT3	788

IntAct

155 interactions, top by confidence:

A	B	Type	Score
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
FSHR	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
WNT3A	FZD8	psi-mi:“MI:0915”(physical association)	0.500
FZD8	WNT3A	psi-mi:“MI:0914”(association)	0.500
FZD8	tcdB	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	GOPC	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI2	FZD8	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2IP	FZD8	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	SNTG1	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP21	FZD8	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	FZD8	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	IL16	psi-mi:“MI:0407”(direct interaction)	0.440
PICK1	FZD8	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
FZD8	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (39): FZD8 (Affinity Capture-Western), FZD8 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), FZD8 (Affinity Capture-RNA), FZD8 (Affinity Capture-MS), FZD8 (Affinity Capture-Western), RNF43 (Affinity Capture-Western), DVL3 (Affinity Capture-Western), FZD8 (Proximity Label-MS), FZD8 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), FZD8 (Affinity Capture-MS)

ESM2 similar proteins: A0A0P0UZP7, B0KZ40, B2DBE9, B6UV92, B8B016, O22241, O70421, O88696, P08196, P0C586, P24322, P37271, P37272, P37294, P49085, P49293, P53797, Q01IJ3, Q08463, Q0DDE3, Q1LVN8, Q28CH3, Q2QLV9, Q2R1U4, Q498S8, Q52QW5, Q5QNM6, Q5VP70, Q5Z5B7, Q5ZJT0, Q61091, Q67UU0, Q6EI12, Q6L534, Q6L5F6, Q6Z1Y6, Q6Z2T8, Q74ZW4, Q7X745, Q7XAP4

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

7 interactions.

A	Effect	B	Mechanism
WNT1	up-regulates	FZD8	binding
RYK	up-regulates	FZD8	binding
FZD8	“up-regulates activity”	LRP5	binding
FZD8	“up-regulates activity”	LRP6	binding
WNT3A	up-regulates	FZD8	binding
ZNRF3	“down-regulates quantity”	FZD8	ubiquitination
hsa-miR-100-3p	“down-regulates quantity by repression”	FZD8	“post transcriptional regulation”

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
Ras activation upon Ca2+ influx through NMDA receptor	5	35.7×	1e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	34.0×	1e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	34.0×	1e-05
Assembly and cell surface presentation of NMDA receptors	10	31.7×	6e-11
Dopamine Neurotransmitter Release Cycle	5	31.0×	2e-05
Long-term potentiation	5	29.7×	2e-05
Neurexins and neuroligins	11	27.1×	5e-11
Protein-protein interactions at synapses	7	23.2×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	56.1×	2e-14
protein localization to synapse	6	40.3×	1e-06
receptor clustering	7	38.3×	2e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	30.4×	6e-07
protein-containing complex assembly	10	10.0×	8e-06
cell-cell adhesion	10	8.9×	2e-05
protein localization to plasma membrane	7	6.7×	3e-03
chemical synaptic transmission	9	6.1×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	78
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

26 predictions. Top by Δscore:

Variant	Effect	Δscore
10:35642158:T:TA	donor_gain	0.6800
10:35642059:T:TA	donor_gain	0.6400
10:35642020:G:A	donor_gain	0.6200
10:35642039:C:CA	donor_gain	0.5600
10:35642276:C:A	donor_gain	0.4300
10:35642275:T:TA	donor_gain	0.3800
10:35640632:GTTGT:G	acceptor_gain	0.3200
10:35642240:T:TA	donor_gain	0.3000
10:35642205:C:CT	donor_gain	0.2900
10:35639662:A:AC	donor_gain	0.2800
10:35639663:C:CC	donor_gain	0.2800
10:35642055:T:TA	donor_gain	0.2700
10:35640615:T:TA	acceptor_gain	0.2600
10:35641872:T:A	donor_gain	0.2600
10:35640621:C:CC	acceptor_gain	0.2500
10:35642202:GGA:G	donor_gain	0.2500
10:35640635:GTGGC:G	acceptor_gain	0.2400
10:35642089:G:T	donor_gain	0.2400
10:35642150:AGTCT:A	donor_gain	0.2400
10:35640168:CA:C	acceptor_gain	0.2300
10:35640633:TTGTG:T	acceptor_gain	0.2100
10:35640706:ACACG:A	donor_gain	0.2100
10:35640707:CACGC:C	donor_gain	0.2100
10:35641636:T:TA	donor_gain	0.2100
10:35640620:G:GC	acceptor_gain	0.2000
10:35642066:T:TA	donor_gain	0.2000

AlphaMissense

4453 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:35639629:C:G	G601R	1.000
10:35639640:C:T	G597D	1.000
10:35639641:C:G	G597R	1.000
10:35639747:C:A	W561C	1.000
10:35639747:C:G	W561C	1.000
10:35639749:A:G	W561R	1.000
10:35639749:A:T	W561R	1.000
10:35639910:A:G	L507P	1.000
10:35639923:C:G	G503R	1.000
10:35639944:C:G	G496R	1.000
10:35640009:C:A	G474V	1.000
10:35640009:C:T	G474D	1.000
10:35640010:C:A	G474C	1.000
10:35640010:C:G	G474R	1.000
10:35640017:G:C	C471W	1.000
10:35640018:C:A	C471F	1.000
10:35640018:C:G	C471S	1.000
10:35640018:C:T	C471Y	1.000
10:35640019:A:G	C471R	1.000
10:35640019:A:T	C471S	1.000
10:35640024:C:A	G469V	1.000
10:35640025:C:A	G469C	1.000
10:35640025:C:G	G469R	1.000
10:35640036:T:A	D465V	1.000
10:35640036:T:C	D465G	1.000
10:35640039:C:T	G464D	1.000
10:35640040:C:A	G464C	1.000
10:35640040:C:G	G464R	1.000
10:35640060:A:G	L457P	1.000
10:35640084:G:C	P449R	1.000

dbSNP variants (sampled 300 via entrez): RS1000117060 (10:35642727 C>G), RS1000524802 (10:35641881 G>A), RS1000551106 (10:35642482 T>G), RS1001282277 (10:35643070 C>G), RS1001514046 (10:35641853 G>A), RS1001931049 (10:35638538 A>C,G), RS1002287975 (10:35642124 C>G,T), RS1002319083 (10:35641928 G>A,T), RS1002527853 (10:35640961 T>G), RS1003393560 (10:35643778 C>A,G,T), RS1003929527 (10:35639486 GCCGCCGCCCCCCGGC>G), RS1004062672 (10:35642144 G>C), RS1004727494 (10:35642268 C>A,T), RS1004912471 (10:35638194 G>C), RS1004984020 (10:35638522 A>G,T)

Disease associations

OMIM: gene MIM:606146 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000189_28	Protein quantitative trait loci	3.000000e-06
GCST001588_12	Periodontal microbiota	2.000000e-06
GCST001613_7	Antineutrophil cytoplasmic antibody-associated vasculitis	9.000000e-06
GCST006193_1	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-10
GCST006194_5	Diastolic blood pressure x smoking status (current vs non-current) interaction (1df test)	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3559689 (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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
vantictumab	Antagonist	8.0	pIC50
carbamazepine	Negative	4.77	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	7
sodium arsenite	decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Atrazine	affects cotreatment, increases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
lead acetate	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
decabromobiphenyl ether	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
kojic acid	increases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	increases expression	1
tetrachlorodian	increases expression	1
deguelin	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
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Arsenates	increases expression, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Camptothecin	decreases methylation	1
Carbamazepine	affects expression	1
Chelating Agents	increases expression, affects binding	1
Cisplatin	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4376175	Binding	Binding affinity to recombinant human Frizzled-8 (Ala25 to Pro172 residues)/human IgG1 chimeric protein expressed in CHO cells assessed as dissociation rate constant 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

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0DJ	Ubigene HeLa FZD8 KO	Cancer cell line	Female
CVCL_SP23	HAP1 FZD8 (-) 1	Cancer cell line	Male
CVCL_SP24	HAP1 FZD8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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