FZD6

Summary

FZD6 (frizzled class receptor 6, HGNC:4044) is a protein-coding gene on chromosome 8q22.3, encoding Frizzled-6 (O60353). Receptor for Wnt proteins.

This gene represents a member of the ‘frizzled’ gene family, which encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The protein encoded by this family member contains a signal peptide, a cysteine-rich domain in the N-terminal extracellular region, and seven transmembrane domains, but unlike other family members, this protein does not contain a C-terminal PDZ domain-binding motif. This protein functions as a negative regulator of the canonical Wnt/beta-catenin signaling cascade, thereby inhibiting the processes that trigger oncogenic transformation, cell proliferation, and inhibition of apoptosis. Alternative splicing results in multiple transcript variants, some of which do not encode a protein with a predicted signal peptide.

Source: NCBI Gene 8323 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic congenital nail disorder 1 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 111 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 8
• MANE Select transcript: NM_003506

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4044
Approved symbol	FZD6
Name	frizzled class receptor 6
Location	8q22.3
Locus type	gene with protein product
Status	Approved
Aliases	Hfz6
Ensembl gene	ENSG00000164930
Ensembl biotype	protein_coding
OMIM	603409
Entrez	8323

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 4 nonsense_mediated_decay

ENST00000358755, ENST00000519011, ENST00000521195, ENST00000522484, ENST00000522566, ENST00000523739, ENST00000523933, ENST00000861009, ENST00000861010, ENST00000861011, ENST00000861012, ENST00000955107

RefSeq mRNA: 4 — MANE Select: NM_003506 NM_001164615, NM_001164616, NM_001317796, NM_003506

CCDS: CCDS55268, CCDS6298

Canonical transcript exons

ENST00000358755 — 7 exons

Exon	Start	End
ENSE00002133745	103331341	103332866
ENSE00003488621	103329655	103330065
ENSE00003509504	103328268	103328416
ENSE00003613314	103318590	103318786
ENSE00003687686	103324481	103325498
ENSE00003844312	103298898	103298995
ENSE00003896182	103299956	103300284

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 95.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.7300 / max 259.9455, expressed in 1591 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90111	16.4638	1584
90112	0.6681	424
90110	0.3147	170
90109	0.2833	155

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	95.07	gold quality
caput epididymis	UBERON:0004358	93.60	gold quality
epithelium of bronchus	UBERON:0002031	93.19	gold quality
choroid plexus epithelium	UBERON:0003911	93.08	gold quality
upper leg skin	UBERON:0004262	92.72	gold quality
bronchus	UBERON:0002185	92.62	gold quality
endometrium epithelium	UBERON:0004811	92.46	gold quality
skin of hip	UBERON:0001554	92.19	gold quality
corpus epididymis	UBERON:0004359	91.37	gold quality
epithelium of nasopharynx	UBERON:0001951	91.12	gold quality
palpebral conjunctiva	UBERON:0001812	91.08	gold quality
secondary oocyte	CL:0000655	90.79	gold quality
hair follicle	UBERON:0002073	89.84	gold quality
stromal cell of endometrium	CL:0002255	88.78	gold quality
penis	UBERON:0000989	88.29	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.29	gold quality
germinal epithelium of ovary	UBERON:0001304	88.25	gold quality
visceral pleura	UBERON:0002401	88.24	gold quality
mammary duct	UBERON:0001765	88.21	gold quality
right uterine tube	UBERON:0001302	88.05	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.78	gold quality
endometrium	UBERON:0001295	87.77	gold quality
islet of Langerhans	UBERON:0000006	87.71	gold quality
lower lobe of lung	UBERON:0008949	87.69	gold quality
oral cavity	UBERON:0000167	87.60	gold quality
skin of abdomen	UBERON:0001416	87.57	gold quality
nasal cavity mucosa	UBERON:0001826	87.41	gold quality
zone of skin	UBERON:0000014	87.28	gold quality
urinary bladder	UBERON:0001255	86.82	gold quality
epithelium of mammary gland	UBERON:0003244	86.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.40
E-ENAD-17	no	83.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, GLI2

miRNA regulators (miRDB)

159 targeting FZD6, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609

Literature-anchored findings (GeneRIF, showing 33)

• Frizzled 6 (HFz6) has a role as a negative regulator of the canonical Wnt. beta-catenin signaling cascade (PMID:14747478)
• These results suggested that activation of Wnt4/Fzd6 signaling through a “beta-catenin-independent” pathway played a role in proliferation and survival of the pituitary adenoma cells. (PMID:19034702)
• No significant association between C345A or A664C SNPs in the FZD6 gene and bone meineral density at skeletal sites measured or circulating levels of bone turnover markers were noted. (PMID:19543507)
• FZD6 mutations can result in severe defects in nail and claw formation through reduced or abolished membranous FZD(6) levels and several nonfunctional WNT-FZD pathways. (PMID:21665003)
• The current study provides insight into the global changes in gene transcription mediated by chr-ECS and suggests that Fzd6 signaling could represent a novel target for development of novel antidepressants. (PMID:21937024)
• This study demonstrates that rare nonsynonymous variants in FZD6 may contribute to NTDs in humans and enlarges the spectrum of mutations that link PCP pathway to Neural tube defects (NTDs). (PMID:22045688)
• Mutations in this gene cause nail dysplasia. Review. (PMID:22078044)
• The present results emphasize the role of FZD6 mutation in Wnt pathways in nail development. (PMID:22211385)
• When transplanted into immunodeficient mice, neuroblastoma cells expressing the Fzd6 marker grow more aggressively than their Fzd6 negative counterparts. Fzd6 is a new surface marker of aggressive neuroblastoma cells with stem cell-like features. (PMID:22249030)
• sequence analysis revealed a novel homozygous missense mutation (c.1266G>A; p.Gly422Asp) located in the transmembrane domain of the protein FZD6 in individuals of a consanguineous family exhibiting features of nail dysplasia (PMID:22861124)
• FZD6 should be screened for pachyonychia congenita as it is a candidate gene for hereditary nail dysplasias. (PMID:23374899)
• It is associated with poor prognosis in glioblastoma patients. (PMID:23748645)
• DVL is a master regulator of FZD6/G-protein signaling (PMID:24500924)
• This study confirms our speculation that down-regulation of FZD6 by beta-Carotene is causally related to the observed up-regulation of cancer related genes (PMID:24657404)
• The rs3808553 of FZD6 is obviously associated with neural tube defects in Han population of northern China (PMID:24816679)
• we found that FZD6 expression was negatively regulated by miR199a5p (PMID:25772759)
• miR-125b/miR-20b and Wnt signalling have roles in glioblastoma phenotypes in a pathway that involves FZD6 (PMID:27698350)
• In this paper we report 3 further families with mutations in FZD6 causing Isolated recessive nail dysplasia. (PMID:27786367)
• the FZD6-fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer (PMID:27859262)
• Study reports a novel pathogenic variant of the FZD6 gene in autosomal recessive nonsyndromic congenital nail disorder in consanguineous Iranian family. (PMID:28545862)
• monomeric rather than dimeric form is active signal initiating unit of the receptor complex; constitutive signaling to ERK1/2 can be affected by modulating the dimeric status (PMID:28790300)
• FZD6 is highly expressed in liver cancer cells and liver tumor-initiating cells.FZD6 is required for liver tumor-initiating cells self-renewal.LncFZD6 interacts and recruits BRG1 to FZD6 promoter to initiate transcription. (PMID:29535420)
• findings demonstrate that suppression of Wnt signaling by upregulation of FZD6 is a mechanism underlying luteolin-induced inhibition of prostate cancer stemness. (PMID:29867083)
• Cys-161, Cys-181, and Cys-185 residues in the linker domain region of FZD6 are crucial for receptor membrane expression and recruitment of DVL2 protein. (PMID:30237173)
• Given the key role of FZD6 in planar cell polarity, our results raise the possibility that asymmetric phosphorylation of FZD6 rather than asymmetric protein distribution accounts for polarized receptor signaling (PMID:30309985)
• Mutations in FZD6 gene were found to be associated with autosomal recessive nail dysplasia. (PMID:30642273)
• The prognostic role of FZD6 in esophageal squamous cell carcinoma patients. (PMID:31748958)
• Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects. (PMID:32356230)
• Mesenchymal stem cell-derived extracellular vesicles suppress the fibroblast proliferation by downregulating FZD6 expression in fibroblasts via micrRNA-29b-3p in idiopathic pulmonary fibrosis. (PMID:32557673)
• MiR-302b Suppresses Tumor Metastasis by Targeting Frizzled 6 in OSCC. (PMID:33478325)
• FZD6 triggers Wnt-signalling driven by WNT10B(IVS1) expression and highlights new targets in T-cell acute lymphoblastic leukemia. (PMID:33497493)
• FZD6 Promotes Melanoma Cell Invasion but Not Proliferation by Regulating Canonical Wnt Signaling and Epithelial-Mesenchymal Transition. (PMID:36368445)
• A novel pathogenic variant in the FZD6 gene causes recessive nail dysplasia in a Moroccan family. (PMID:37401642)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fzd6	ENSDARG00000104874
mus_musculus	Fzd6	ENSMUSG00000022297
rattus_norvegicus	Fzd6	ENSRNOG00000004660

Paralogs (15): FZD3 (ENSG00000104290), SFRP1 (ENSG00000104332), SFRP4 (ENSG00000106483), FZD10 (ENSG00000111432), SFRP5 (ENSG00000120057), SMO (ENSG00000128602), SFRP2 (ENSG00000145423), FZD7 (ENSG00000155760), FZD1 (ENSG00000157240), FRZB (ENSG00000162998), FZD5 (ENSG00000163251), FZD4 (ENSG00000174804), FZD8 (ENSG00000177283), FZD2 (ENSG00000180340), FZD9 (ENSG00000188763)

Protein

Protein identifiers

Frizzled-6 — O60353 (reviewed: O60353)

All UniProt accessions (5): E5RGK8, E5RJG0, O60353, E5RJT4, G5EA13

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. Together with FZD3, is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear.

Subunit / interactions. Interacts with LMBR1L.

Subcellular location. Membrane. Cell membrane. Cell surface. Apical cell membrane. Cytoplasmic vesicle membrane. Endoplasmic reticulum membrane.

Tissue specificity. Detected in adult heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, thymus, prostate, testis, ovary, small intestine and colon. In the fetus, expressed in brain, lung, liver and kidney.

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

Disease relevance. Nail disorder, non-syndromic congenital, 1 (NDNC1) [MIM:161050] An autosomal recessive nail disorder characterized by a variable degree of onychauxis (thick nails), hyponychia, and onycholysis of all nails, with claw-shaped fingernails in some individuals. No other anomalies of ectodermal tissues, including hair, teeth, sweat glands, or skin, are noted, and individuals with dysplastic nails have normal hearing and normal psychomotor development. The disease is caused by variants affecting the gene represented in this entry. Rare non-synonymous variants in FZD6 may contribute to neural tube defects, congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy.

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.

Isoforms (2)

UniProt ID	Names	Canonical?
O60353-1	1	yes
O60353-2	2

RefSeq proteins (4): NP_001158087, NP_001158088, NP_001304725, NP_003497* (*=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
IPR026543	FZD6_7TM	Domain
IPR036790	Frizzled_dom_sf	Homologous_superfamily
IPR041770	FZ6_CRD	Domain

Pfam: PF01392, PF01534

UniProt features (74 total): helix 15, sequence variant 11, strand 10, topological domain 8, transmembrane region 7, disulfide bond 5, turn 5, compositionally biased region 4, glycosylation site 2, signal peptide 1, chain 1, domain 1, region of interest 1, short sequence motif 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8JH7	ELECTRON MICROSCOPY	3.2
8JHB	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60353-F1	73.19	0.38

Antibody-complex structures (SAbDab): 2 — 8JH7, 8JHB

Functional residue map

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

Post-translational modifications (1): 653

Disulfide bonds (5): 24–85, 32–78, 69–106, 95–129, 99–123

Glycosylation sites (2): 38, 352

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-4086398	Ca2+ pathway
R-HSA-4086400	PCP/CE pathway
R-HSA-4641263	Regulation of FZD by ubiquitination
R-HSA-5340588	Signaling by RNF43 mutants

MSigDB gene sets: 312 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, VERHAAK_AML_WITH_NPM1_MUTATED_DN, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GOBP_PLATELET_ACTIVATION, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, BEIER_GLIOMA_STEM_CELL_DN, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), neural tube closure (GO:0001843), hair follicle development (GO:0001942), platelet activation (GO:0030168), cell proliferation in midbrain (GO:0033278), non-canonical Wnt signaling pathway (GO:0035567), embryonic nail plate morphogenesis (GO:0035880), inner ear morphogenesis (GO:0042472), establishment of body hair planar orientation (GO:0048105), canonical Wnt signaling pathway (GO:0060070), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), negative regulation of canonical Wnt signaling pathway (GO:0090090), midbrain morphogenesis (GO:1904693), establishment of planar polarity (GO:0001736), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), Wnt signaling pathway (GO:0016055), midbrain development (GO:0030901)

GO Molecular Function (6): G protein-coupled receptor activity (GO:0004930), Wnt-protein binding (GO:0017147), ubiquitin protein ligase binding (GO:0031625), Wnt receptor activity (GO:0042813), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (12): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), cilium (GO:0005929), cell surface (GO:0009986), apical plasma membrane (GO:0016324), apicolateral plasma membrane (GO:0016327), cytoplasmic vesicle membrane (GO:0030659), ciliary basal body (GO:0036064), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), apical part of cell (GO:0045177)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Beta-catenin independent WNT signaling	2
GPCR ligand binding	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
cellular anatomical structure	3
anatomical structure development	2
midbrain development	2
embryonic morphogenesis	2
signal transduction	2
transmembrane signaling receptor activity	2
plasma membrane region	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
primary neural tube formation	1
tube closure	1
hair cycle process	1
skin epidermis development	1
cell activation	1
blood coagulation	1
neural precursor cell proliferation	1
nail development	1
embryonic digit morphogenesis	1
ear morphogenesis	1
inner ear development	1
establishment of body hair or bristle planar orientation	1
non-canonical Wnt signaling pathway	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
anatomical structure morphogenesis	1
brain morphogenesis	1
morphogenesis of a polarized epithelium	1
establishment of tissue polarity	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
brain development	1

Protein interactions and networks

STRING

1186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FZD6	WNT5A	P41221	991
FZD6	WNT11	O96014	986
FZD6	CELSR1	Q9NYQ6	980
FZD6	VANGL2	Q9ULK5	966
FZD6	WNT4	P56705	943
FZD6	VANGL1	Q8TAA9	933
FZD6	WNT5B	Q9H1J7	894
FZD6	DVL1	O14640	888
FZD6	WNT7A	O00755	883
FZD6	WNT7B	P56706	797
FZD6	DVL2	O14641	790
FZD6	LRP6	O75581	790
FZD6	WNT16	Q9UBV4	782
FZD6	WNT3A	P56704	759
FZD6	DVL3	Q92997	758

IntAct

73 interactions, top by confidence:

A	B	Type	Score
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
NPTX2	FZD6	psi-mi:“MI:0915”(physical association)	0.560
NPTX2	FZD6	psi-mi:“MI:0403”(colocalization)	0.560
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
GABRE	FZD6	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
TMPRSS12	FZD6	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
CYB5D2	ABLIM1	psi-mi:“MI:0914”(association)	0.530
ZNRF3	FZD6	psi-mi:“MI:0915”(physical association)	0.400
FZD6	SFRP1	psi-mi:“MI:0915”(physical association)	0.400
SFRP1	FZD6	psi-mi:“MI:0915”(physical association)	0.400
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (78): FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Proximity Label-MS), FZD6 (Proximity Label-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), FZD6 (Proximity Label-MS)

ESM2 similar proteins: A0A084B9Z2, A0A0A2JY25, A0A0D1E6B3, A0A0R8YXT5, A0A142I738, A0A2I1CSG1, A0A2L0P0K0, A0A348HAY3, A1CIM4, B2KWI0, G1X9E2, G1X9H9, G1XJN1, G5EDW2, I1RLA6, O13780, O13880, O42579, O60353, P0DUT8, P13773, P31302, P31303, P31397, P49190, P70555, P78741, P9WEL3, P9WEU1, P9WEV3, Q05659, Q09460, Q0CRW7, Q0V6Q8, Q12256, Q2KI97, Q4D3E8, Q4G2T3, Q4WR17, Q54ET0

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
WNT11	“up-regulates activity”	FZD6	binding
WNT5A	“up-regulates activity”	FZD6	binding
WNT5B	up-regulates	FZD6	binding
FZD6	“up-regulates activity”	DVL1	binding
WNT1	“up-regulates activity”	FZD6	binding
ZNRF3	“down-regulates quantity”	FZD6	ubiquitination
hsa-miR-199a-5p	“down-regulates quantity by repression”	FZD6	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 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
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	11.8×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	83
Likely benign	8
Benign	3

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
30355	NM_003506.4(FZD6):c.1750G>T (p.Glu584Ter)	Pathogenic
30356	NM_003506.4(FZD6):c.1531C>T (p.Arg511Cys)	Pathogenic
3775575	NM_003506.4(FZD6):c.1622del (p.Lys541fs)	Pathogenic
438765	NM_003506.4(FZD6):c.346C>T (p.Arg116Ter)	Pathogenic
827757	NM_003506.4(FZD6):c.1525C>T (p.Arg509Ter)	Pathogenic
827759	NM_003506.4(FZD6):c.1312G>A (p.Glu438Lys)	Pathogenic
993016	NM_003506.4(FZD6):c.1393-2A>G	Likely pathogenic

SpliceAI

1337 predictions. Top by Δscore:

Variant	Effect	Δscore
8:103300282:GAG:G	donor_gain	1.0000
8:103300283:AGG:A	donor_loss	1.0000
8:103300284:GGT:G	donor_loss	1.0000
8:103300285:G:GC	donor_loss	1.0000
8:103300286:T:A	donor_loss	1.0000
8:103318589:GC:G	acceptor_gain	1.0000
8:103318608:A:G	acceptor_gain	1.0000
8:103324620:GGATA:G	donor_gain	1.0000
8:103324621:GATA:G	donor_gain	1.0000
8:103328413:GAGA:G	donor_gain	1.0000
8:103328415:GA:G	donor_gain	1.0000
8:103328417:G:GG	donor_gain	1.0000
8:103329653:A:AG	acceptor_gain	1.0000
8:103329654:G:GA	acceptor_gain	1.0000
8:103300155:AAGAG:A	acceptor_gain	0.9900
8:103300156:A:G	acceptor_gain	0.9900
8:103300280:TGGAG:T	donor_gain	0.9900
8:103300281:GGAG:G	donor_gain	0.9900
8:103300281:GGAGG:G	donor_gain	0.9900
8:103300282:GAGG:G	donor_gain	0.9900
8:103300285:G:GG	donor_gain	0.9900
8:103306325:T:TA	donor_gain	0.9900
8:103306326:A:AA	donor_gain	0.9900
8:103318588:A:AG	acceptor_gain	0.9900
8:103318589:G:GG	acceptor_gain	0.9900
8:103318589:GCA:G	acceptor_gain	0.9900
8:103318589:GCATT:G	acceptor_gain	0.9900
8:103318607:A:AG	acceptor_gain	0.9900
8:103318612:T:TA	acceptor_gain	0.9900
8:103318783:ACAG:A	donor_gain	0.9900

AlphaMissense

4647 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:103324785:T:C	F227L	1.000
8:103324787:C:A	F227L	1.000
8:103324787:C:G	F227L	1.000
8:103324764:T:C	F220L	0.999
8:103324766:T:A	F220L	0.999
8:103324766:T:G	F220L	0.999
8:103324786:T:C	F227S	0.999
8:103325001:T:A	W299R	0.999
8:103325001:T:C	W299R	0.999
8:103325004:T:A	W300R	0.999
8:103325004:T:C	W300R	0.999
8:103325025:T:A	W307R	0.999
8:103325025:T:C	W307R	0.999
8:103325100:T:A	W332R	0.999
8:103325100:T:C	W332R	0.999
8:103325335:T:C	L410P	0.999
8:103325344:T:C	F413S	0.999
8:103325367:A:C	S421R	0.999
8:103325369:C:A	S421R	0.999
8:103325369:C:G	S421R	0.999
8:103328352:T:A	W493R	0.999
8:103328352:T:C	W493R	0.999
8:103328382:T:A	W503R	0.999
8:103328382:T:C	W503R	0.999
8:103318763:G:C	W117C	0.998
8:103318763:G:T	W117C	0.998
8:103324786:T:G	F227C	0.998
8:103324792:A:G	Y229C	0.998
8:103324794:C:T	P230S	0.998
8:103324795:C:A	P230Q	0.998

dbSNP variants (sampled 300 via entrez): RS1000011379 (8:103302443 A>G), RS1000018037 (8:103305663 T>C), RS1000500836 (8:103311018 G>A), RS1000674146 (8:103298359 A>G), RS1000743575 (8:103296520 G>A,C), RS1000767893 (8:103320768 C>T), RS1001098870 (8:103307082 C>T), RS1001103495 (8:103325545 A>G), RS1001130432 (8:103297916 T>C), RS1001146475 (8:103324112 T>A), RS1001283309 (8:103304275 A>C,G), RS1001359011 (8:103331430 A>G), RS1001490410 (8:103332481 T>G), RS1001520161 (8:103332113 T>A,C), RS1001537268 (8:103311767 GTTC>G)

Disease associations

OMIM: gene MIM:603409 | disease phenotypes: MIM:161050, MIM:236750

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic congenital nail disorder 1	Definitive	Autosomal recessive
autosomal recessive nail dysplasia	Strong	Autosomal recessive
hydrops fetalis	Strong	Autosomal recessive

Mondo (7): nonsyndromic congenital nail disorder 1 (MONDO:0008060), non-immune hydrops fetalis (MONDO:0009369), nail disorder (MONDO:0002884), Wilms tumor (MONDO:0006058), primary amenorrhea (MONDO:1060208), (MONDO:0029051), hydrops fetalis (MONDO:0015193)

Orphanet (4): Autosomal recessive nail dysplasia (Orphanet:280654), Idiopathic trachyonychia (Orphanet:79153), Non-immune hydrops fetalis (Orphanet:363999), Nephroblastoma (Orphanet:654)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001805	Onychogryphosis
HP:0001806	Onycholysis
HP:0002164	Nail dysplasia
HP:0003577	Congenital onset
HP:0003677	Slowly progressive
HP:0012542	Onychauxis
HP:0030804	Trachyonychia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009615_8	Triglyceride levels x loop diuretics use interaction	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D015160	Hydrops Fetalis	C12.050.703.277.060.480; C15.378.295.480; C15.378.420.826.100.350; C16.300.060.480; C16.320.365.826.100.350; C20.306.480; C23.888.277.395
D009260	Nail Diseases	C17.800.529
D009396	Wilms Tumor	C04.557.435.595; C04.588.945.947.535.585; C04.700.900; C12.050.351.937.820.535.585; C12.050.351.968.419.473.585; C12.200.758.820.750.585; C12.200.777.419.473.585; C12.900.820.535.585; C12.950.419.473.585; C12.950.983.535.585; C16.320.700.900
C562907	Twenty-Nail Dystrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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
SAG1.3	Partial agonist	5.6	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	4
sodium arsenite	affects methylation, decreases expression	3
Air Pollutants	decreases expression, increases abundance	3
Smoke	decreases expression, increases abundance	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
potassium chromate(VI)	increases expression	1
ferrous chloride	decreases expression	1
nickel sulfate	increases expression	1
coumarin	decreases phosphorylation	1
perfluorooctane sulfonic acid	decreases expression	1
entinostat	increases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
imeglimin	increases expression	1
Vorinostat	increases expression	1
Glyphosate	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Bleomycin	decreases reaction, increases expression	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Coal	decreases expression, increases abundance	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1SI	Abcam HeLa FZD6 KO	Cancer cell line	Female
CVCL_E0DH	Ubigene HeLa FZD6 KO	Cancer cell line	Female
CVCL_SP19	HAP1 FZD6 (-) 1	Cancer cell line	Male
CVCL_SP20	HAP1 FZD6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01330706	PHASE4	COMPLETED	Efficacy of Intraoperative Surgical Scrubbing in Reducing Bacterial Load After Nail Removal Surgery
NCT03991936	PHASE4	COMPLETED	Benefit of Placebo and Different Concentrations of Triamcinolone Acetonide in Nail Psoriasis
NCT04384679	PHASE4	WITHDRAWN	Benefit of Topical Hemostatic Powder Containing Hydrophilic Polymer With Potassium Ferrate for Hemostasis Following Nail Surgery
NCT04422795	PHASE4	WITHDRAWN	The Evaluation of External Thermomechanical Stimulation for Pain Reduction in Patients Undergoing Nail Injection
NCT04941807	PHASE4	COMPLETED	Use of Platelet-rich Plasma (PRP) Therapy in Patients With Brittle Nail Syndrome
NCT05544734	PHASE4	COMPLETED	Hydrocodone Compared to Acetaminophen and Ibuprofen for Post-nail Procedure Analgesia
NCT00336531	PHASE4	COMPLETED	Efficacy of Prophylactic Itraconazole in High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation
NCT00925418	PHASE3	COMPLETED	Evaluation of the Cryotherapy in the Prevention of Nails Toxicity Induced by Taxotere® in Breast or Prostate Cancer
NCT00038207	PHASE2	COMPLETED	Liposomal Vincristine for Pediatric and Adolescent Patients With Relapsed Malignancies
NCT00141765	PHASE2	COMPLETED	Study of High-Dose Chemotherapy With Bone Marrow or Stem Cell Transplant for Rare Poor-Prognosis Cancers
NCT00187031	PHASE2	COMPLETED	A Phase II Study of Topotecan in Children With Recurrent Wilms Tumor
NCT01095926	PHASE2	COMPLETED	Pharmacokinetic Study of Doxorubicin in Children With Cancer
NCT02452554	PHASE2	COMPLETED	Lorvotuzumab Mertansine in Treating Younger Patients With Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma
NCT02624388	PHASE2	TERMINATED	Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT02867592	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04791228	PHASE2	WITHDRAWN	A Pilot Study of Thermodox and MR-HIFU for Treatment of Relapsed Solid Tumors
NCT04968990	PHASE2	RECRUITING	Treatment of Newly Diagnosed Patient’s With Wilm’s Tumor Requiring Abdominal Radiation Delivered With Proton Beam Irradiation
NCT05302921	PHASE2	COMPLETED	Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors
NCT05985161	PHASE2	RECRUITING	A Study of Selinexor in People With Wilms Tumors and Other Solid Tumors
NCT02986698	PHASE1	TERMINATED	In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)
NCT00011414	PHASE1	COMPLETED	Phase I Trial of Tariquidar (XR9576) in Combination With Doxorubicin, Vinorelbine, or Docetaxel in Pediatric Patients With Solid Tumors
NCT00436657	PHASE1	COMPLETED	Continuous Hyperthermic Peritoneal Perfusion (CHPP) With Cisplatin for Children With Peritoneal Cancer
NCT00931931	PHASE1	COMPLETED	HSV1716 in Patients With Non-Central Nervous System (Non-CNS) Solid Tumors
NCT01130623	PHASE1	WITHDRAWN	A Phase I Study of Pazopanib as a Single Agent for Children With Refractory Solid Tumors
NCT01222780	PHASE1	COMPLETED	To Evaluate the Safety, Activity and Pharmacokinetics of Marqibo in Children and Adolescents With Refractory Cancer
NCT01331135	PHASE1	COMPLETED	Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors
NCT01625351	PHASE1	COMPLETED	A Study of CD45RA+ Depleted Haploidentical Stem Cell Transplantation in Children With Relapsed or Refractory Solid Tumors and Lymphomas
NCT01661400	PHASE1	COMPLETED	Anti-Angiogenic Therapy Post Transplant (ASCR) for Pediatric Solid Tumors
NCT02076906	PHASE1	COMPLETED	MR-guided High Intensity Focused Ultrasound (HIFU) on Pediatric Solid Tumors