ZNRF3

Summary

ZNRF3 (zinc and ring finger 3, HGNC:18126) is a protein-coding gene on chromosome 22q12.1, encoding E3 ubiquitin-protein ligase ZNRF3 (Q9ULT6). E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6.

Enables frizzled binding activity and ubiquitin-protein transferase activity. Involved in negative regulation of Wnt signaling pathway; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in plasma membrane.

Source: NCBI Gene 84133 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 71
• Clinical variants (ClinVar): 163 total — 7 pathogenic
• Phenotypes (HPO): 29
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_001206998

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18126
Approved symbol	ZNRF3
Name	zinc and ring finger 3
Location	22q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1133, BK747E2.3, FLJ22057, RNF203
Ensembl gene	ENSG00000183579
Ensembl biotype	protein_coding
OMIM	612062
Entrez	84133

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000402174, ENST00000406323, ENST00000544604, ENST00000885693, ENST00000920449, ENST00000920450, ENST00000920451, ENST00000920452, ENST00000962449

RefSeq mRNA: 2 — MANE Select: NM_001206998 NM_001206998, NM_032173

CCDS: CCDS42999, CCDS56225

Canonical transcript exons

ENST00000544604 — 9 exons

Exon	Start	End
ENSE00001303328	29043299	29043430
ENSE00001308098	29049197	29050948
ENSE00001309159	29046716	29046883
ENSE00001322179	29044780	29044890
ENSE00001325812	29048389	29048491
ENSE00001329477	29042495	29042569
ENSE00001427475	29053579	29057488
ENSE00002312639	28883572	28884066
ENSE00003547707	28987076	28987201

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 97.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.2867 / max 53.9716, expressed in 1516 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191583	4.1744	1457
191581	0.6882	397
191582	0.4241	250

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	97.28	gold quality
caput epididymis	UBERON:0004358	97.04	gold quality
kidney epithelium	UBERON:0004819	95.51	gold quality
seminal vesicle	UBERON:0000998	89.30	gold quality
cauda epididymis	UBERON:0004360	88.55	gold quality
adult organism	UBERON:0007023	88.44	gold quality
cerebellar vermis	UBERON:0004720	88.20	gold quality
endothelial cell	CL:0000115	86.79	silver quality
entorhinal cortex	UBERON:0002728	86.11	gold quality
germinal epithelium of ovary	UBERON:0001304	85.72	gold quality
upper leg skin	UBERON:0004262	85.57	gold quality
renal medulla	UBERON:0000362	85.07	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.53	gold quality
skin of hip	UBERON:0001554	84.45	gold quality
visceral pleura	UBERON:0002401	84.43	gold quality
postcentral gyrus	UBERON:0002581	84.25	gold quality
parietal pleura	UBERON:0002400	83.72	gold quality
parietal lobe	UBERON:0001872	82.99	gold quality
superior frontal gyrus	UBERON:0002661	82.63	gold quality
metanephros	UBERON:0000081	82.47	gold quality
tibialis anterior	UBERON:0001385	81.88	silver quality
pigmented layer of retina	UBERON:0001782	81.81	gold quality
primary visual cortex	UBERON:0002436	81.75	gold quality
kidney	UBERON:0002113	81.74	gold quality
parotid gland	UBERON:0001831	81.69	gold quality
upper arm skin	UBERON:0004263	81.58	silver quality
occipital lobe	UBERON:0002021	81.13	gold quality
epithelial cell of pancreas	CL:0000083	81.07	gold quality
lower lobe of lung	UBERON:0008949	80.71	gold quality
placenta	UBERON:0001987	80.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	78.37
E-ANND-3	yes	11.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

317 targeting ZNRF3, 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-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-371A-3P	99.99	66.77	91
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-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487

Literature-anchored findings (GeneRIF, showing 31)

• study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration (PMID:22575959)
• ZNRF3 inhibits gastric cancer cell growth and promotes cell apoptosis by affecting the Wnt/beta-catenin/TCF4 signalling pathway. (PMID:23504200)
• Genes within recently identified loci associated with waist-hip ratio (WHR) exhibit fat depot-specific mRNA expression, which correlates with obesity-related traits. Adipose tissue (AT) mRNA expression of 6 genes (TBX15/WARS2, STAB1, PIGC, ZNRF3, GRB14 (PMID:23670221)
• Signalling potency of R-spondin proteins depends on their ability to recruit ZNRF3 or RNF43 via Fu1 into a complex with LGR receptors, which interact with Rspo via Fu2 (PMID:24225776)
• ZNRF3 binds RSPO1 and LGR5-RSPO1 with micromolar affinity via RSPO1 furin-like 1 (Fu1) domain. (PMID:24349440)
• Data indicate Dishevelled (DVL) as a dual function adaptor to recruit negative regulators ZNRF3/RNF43 to Wnt receptors to ensure proper control of pathway activity. (PMID:25891077)
• ZnRF3 negatively influences both the Wnt and Hedgehog proliferative pathways and probably this way it negatively regulates cancer progression (PMID:25923840)
• miR-93/ZNRF3/Wnt/beta-catenin regulatory network contributes to the growth of lung carcinoma. (PMID:26423400)
• Report shows that miR-146b participated in migration, invasion and chemoresistance in osteosarcoma via downregulation of ZNRF3. (PMID:26549292)
• ZnRF3 negatively influences both the Wnt and Hedgehog proliferative pathways, and probably this way it negatively regulates cancer progression. (PMID:27352324)
• Data indicate that clinical specimens showed a significant inverse correlation between zinc and ring finger 3 (ZNRF3) and beta-catenin mRNA levels. (PMID:27448298)
• Data suggest that inactivation of RNF43 and ZNRF3 is important in serrated tumorigenesis and has identified a potential therapeutic strategy for this cancer subtype. (PMID:27661107)
• ZNRF3 inhibited the metastasis and tumorigenesis via suppressing the Wnt/beta-catenin signaling pathway in NPC cells. (PMID:27733215)
• The ZNRF3 is ubiquitinated by beta-TRCP in both CKI-phosphorylation- and degron-dependent manners. (PMID:29497989)
• Missense variants of ZNRF3 are associated with Disorders of Sex Development. (PMID:29735715)
• results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification; these findings have direct implications for regenerative medicine and WNT-associated cancers (PMID:29769720)
• The present study suggests rs7290117 in ZNRF3 may be involved in the regulation of axial length, though our results do not support a contribution of the SNPs we tested in ZNRF3, HGF and MFRP to primary angle-closure glaucoma in northern Chinese people (PMID:30348125)
• The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer. (PMID:31934854)
• MicroRNA301a/ZNRF3/wnt/betacatenin signal regulatory crosstalk mediates glioma progression. (PMID:33367931)
• Low Protein Expression of both ATRX and ZNRF3 as Novel Negative Prognostic Markers of Adult Adrenocortical Carcinoma. (PMID:33513905)
• RSPO2 silence inhibits tumorigenesis of nasopharyngeal carcinoma by ZNRF3/Hedgehog-Gli1 signal pathway. (PMID:34273374)
• A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling. (PMID:34590584)
• A positive feedback loop of lncRNA-RMRP/ZNRF3 axis and Wnt/beta-catenin signaling regulates the progression and temozolomide resistance in glioma. (PMID:34657141)
• Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse. (PMID:34716314)
• RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state. (PMID:35039505)
• Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development. (PMID:36631813)
• Single-Exon Deletions of ZNRF3 Exon 2 Cause Congenital Adrenal Hypoplasia. (PMID:37878959)
• Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth. (PMID:38056465)
• Comprehensive analysis of zinc and ring finger 3 in prognostic value and pan-cancer immunity. (PMID:38457275)
• E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled receptors. (PMID:38969364)
• Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/beta-catenin signaling. (PMID:39168120)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	znrf3	ENSDARG00000062573
mus_musculus	Znrf3	ENSMUSG00000041961
rattus_norvegicus	Znrf3	ENSRNOG00000067305

Paralogs (1): RNF43 (ENSG00000108375)

Protein

Protein identifiers

E3 ubiquitin-protein ligase ZNRF3 — Q9ULT6 (reviewed: Q9ULT6)

Alternative names: RING finger protein 203, RING-type E3 ubiquitin transferase ZNRF3, Zinc/RING finger protein 3

All UniProt accessions (1): Q9ULT6

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby restricting the size of the intestinal stem cell zone. Along with RSPO2 and RNF43, constitutes a master switch that governs limb specification.

Subunit / interactions. Interacts with LRP6, FZD4, FZD5, FZD6 and FZD8. Interacts with RSPO1; interaction promotes indirect interaction with LGR4 and membrane clearance of ZNRF3. Also interacts with RSPO2. Interacts with LMBR1L.

Subcellular location. Cell membrane.

Activity regulation. Negatively regulated by R-spondin proteins such as RSPO1: interaction with RSPO1 induces the indirect association between ZNRF3 and LGR4, promoting membrane clearance of ZNRF3.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ZNRF3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9ULT6-1	1	yes
Q9ULT6-2	2

RefSeq proteins (2): NP_001193927, NP_115549 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR040700	ZNRF-3_ecto	Domain
IPR045903	ZNRF3_Znf_RING	Domain
IPR051073	ZNRF3_Arkadia_E3_ligases	Family

Pfam: PF13639, PF18212

UniProt features (34 total): strand 9, helix 9, region of interest 5, compositionally biased region 3, topological domain 2, signal peptide 1, chain 1, splice variant 1, mutagenesis site 1, transmembrane region 1, zinc finger region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8G4Y	X-RAY DIFFRACTION	1.41
8XFS	ELECTRON MICROSCOPY	3.2
8XFP	ELECTRON MICROSCOPY	3.21
8XFT	ELECTRON MICROSCOPY	3.24
9KB8	ELECTRON MICROSCOPY	3.25
8Y69	ELECTRON MICROSCOPY	3.38
9KB9	ELECTRON MICROSCOPY	3.59
4UFS	X-RAY DIFFRACTION	4.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULT6-F1	51.30	0.10

Antibody-complex structures (SAbDab): 4 — 8XFP, 8XFS, 8XFT, 8Y69

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
103	abolishes interaction with rspo1 and prevents subsequent membrane clearance.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-4641263	Regulation of FZD by ubiquitination

MSigDB gene sets: 264 (showing top): PEREZ_TP63_TARGETS, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_STEM_CELL_PROLIFERATION, FOSTER_TOLERANT_MACROPHAGE_UP, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_APPENDAGE_DEVELOPMENT, GOBP_RECEPTOR_METABOLIC_PROCESS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, CHIANG_LIVER_CANCER_SUBCLASS_INTERFERON_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING

GO Biological Process (12): ubiquitin-dependent protein catabolic process (GO:0006511), Wnt signaling pathway (GO:0016055), protein ubiquitination (GO:0016567), Wnt receptor catabolic process (GO:0038018), limb development (GO:0060173), stem cell proliferation (GO:0072089), negative regulation of canonical Wnt signaling pathway (GO:0090090), negative regulation of non-canonical Wnt signaling pathway (GO:2000051), regulation of Wnt signaling pathway, planar cell polarity pathway (GO:2000095), negative regulation of Wnt signaling pathway (GO:0030178), regulation of canonical Wnt signaling pathway (GO:0060828), regulation of non-canonical Wnt signaling pathway (GO:2000050)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), frizzled binding (GO:0005109), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of Wnt signaling pathway	3
regulation of Wnt signaling pathway	3
canonical Wnt signaling pathway	2
non-canonical Wnt signaling pathway	2
regulation of non-canonical Wnt signaling pathway	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell surface receptor signaling pathway	1
protein modification by small protein conjugation	1
receptor catabolic process	1
appendage development	1
cell population proliferation	1
stem cell division	1
regulation of canonical Wnt signaling pathway	1
Wnt signaling pathway, planar cell polarity pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
ubiquitin-like protein transferase activity	1
G protein-coupled receptor binding	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

927 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZNRF3	LGR4	Q9BXB1	995
ZNRF3	RSPO1	Q2MKA7	988
ZNRF3	PCGF3	Q3KNV8	968
ZNRF3	LGR5	O75473	941
ZNRF3	RSPO2	Q6UXX9	881
ZNRF3	LRP6	O75581	790
ZNRF3	LRP5	O75197	768
ZNRF3	LGR6	Q9HBX8	764
ZNRF3	RNF43	Q68DV7	759
ZNRF3	RSPO4	Q2I0M5	740
ZNRF3	RSPO3	Q9BXY4	725
ZNRF3	DKK1	O94907	718
ZNRF3	DVL1	O14640	713
ZNRF3	AXIN2	Q9Y2T1	635
ZNRF3	CTNNB1	P35222	635

IntAct

32 interactions, top by confidence:

A	B	Type	Score
RSPO1	ZNRF3	psi-mi:“MI:0407”(direct interaction)	0.700
ZNRF3	RSPO1	psi-mi:“MI:0407”(direct interaction)	0.700
ZNRF3	RSPO1	psi-mi:“MI:0914”(association)	0.700
ZNRF3	RSPO1	psi-mi:“MI:0915”(physical association)	0.700
TTMP	ZNRF3	psi-mi:“MI:0915”(physical association)	0.560
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
ZNRF3	LGR4	psi-mi:“MI:0915”(physical association)	0.500
ZNRF3	LRP6	psi-mi:“MI:0915”(physical association)	0.400
ZNRF3	FZD6	psi-mi:“MI:0915”(physical association)	0.400
ZNRF3	Fzd8	psi-mi:“MI:0915”(physical association)	0.400
ZNRF3	UBE2N	psi-mi:“MI:0915”(physical association)	0.370
ZNRF3	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
ZNRF3	HSPB1	psi-mi:“MI:0915”(physical association)	0.370
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
NRSN1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
MARCHF1	STXBP3	psi-mi:“MI:0914”(association)	0.350
KCNE3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
ZNRF3	ITGA8	psi-mi:“MI:0914”(association)	0.350
SLC1A6	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC20A2	MEIOC	psi-mi:“MI:0914”(association)	0.350
SLC30A5	NBAS	psi-mi:“MI:0914”(association)	0.350
SLC30A8	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
SLC9A5	NBAS	psi-mi:“MI:0914”(association)	0.350

BioGRID (74): DVL2 (Affinity Capture-Western), ZNRF3 (Two-hybrid), ZNRF3 (FRET), ZNRF3 (FRET), ZNRF3 (FRET), RSPO2 (Reconstituted Complex), RSPO3 (Reconstituted Complex), RSPO1 (Reconstituted Complex), ZNRF3 (Co-crystal Structure), ZNRF3 (Affinity Capture-Western), ZNRF3 (Affinity Capture-Western), FZD7 (Affinity Capture-Western), RSPO1 (Reconstituted Complex), RSPO2 (Reconstituted Complex), RSPO3 (Reconstituted Complex)

ESM2 similar proteins: A0A1L8I316, A0A286YDK6, A2A8T7, A5WWA0, A6H7B4, A6NFA0, A6NFR6, A6NGY1, A6NKB5, A6QP24, A8MX80, B2RQL2, O93343, P0C6A0, Q0VD86, Q1EHW4, Q1RN00, Q2HR82, Q32LI3, Q32LN6, Q3B8N5, Q49AJ0, Q5BMD4, Q5DU28, Q5NCP0, Q5SSZ7, Q64ET8, Q66H53, Q68DV7, Q68US1, Q6P4J6, Q6PE65, Q6PG16, Q7SYV9, Q80U22, Q80VY2, Q80W69, Q8BII1, Q8K2F3, Q8N2Y8

Diamond homologs: A5WWA0, E9QAU8, G3X9R7, O22197, O22755, O43567, O54965, O64763, P0C034, P0CH30, P0DPR2, Q06003, Q07G42, Q08D68, Q0II22, Q0VD51, Q10R93, Q14B02, Q29RU0, Q2TA44, Q3U2C5, Q4KLR8, Q4R6Y5, Q5NCP0, Q5RCV8, Q5RF74, Q5SPX3, Q5SSZ7, Q5XF85, Q641J8, Q66HG0, Q68DV7, Q69U49, Q6AY01, Q6DIP3, Q6IRP0, Q6NML0, Q6NQG7, Q6NRX0, Q6Y290

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
ZNRF3	“down-regulates quantity by destabilization”	FZD2	ubiquitination
ZNRF3	down-regulates	FZD2	ubiquitination
ZNRF3	down-regulates	LRP6	ubiquitination
RSPO1	down-regulates	ZNRF3	relocalization
ZNRF3	down-regulates	FZD2	relocalization
PTPRK	“up-regulates activity”	ZNRF3	dephosphorylation
ZNRF3	“down-regulates quantity”	FZD8	ubiquitination
ZNRF3	“down-regulates quantity”	LRP6	ubiquitination
RSPO1	“down-regulates quantity”	ZNRF3	relocalization
ZNRF3	“down-regulates quantity”	FZD6	ubiquitination
ZNRF3	“down-regulates quantity”	FZD4	ubiquitination
ZNRF3	“down-regulates quantity”	FZD5	ubiquitination
Ub:E2	“up-regulates activity”	ZNRF3	ubiquitination

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — ACC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	0
Uncertain significance	125
Likely benign	11
Benign	2

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3238957	NM_001206998.2(ZNRF3):c.311T>C (p.Leu104Pro)	Pathogenic
3238960	NM_001206998.2(ZNRF3):c.536C>T (p.Pro179Leu)	Pathogenic
3238962	NM_001206998.2(ZNRF3):c.887G>A (p.Cys296Tyr)	Pathogenic
3238963	NM_001206998.2(ZNRF3):c.920G>A (p.Arg307Gln)	Pathogenic
3238964	NM_001206998.2(ZNRF3):c.956G>A (p.Cys319Tyr)	Pathogenic
3238965	NM_001206998.2(ZNRF3):c.965C>G (p.Pro322Arg)	Pathogenic
3238966	NM_001206998.2(ZNRF3):c.1000C>T (p.Arg334Trp)	Pathogenic

SpliceAI

1968 predictions. Top by Δscore:

Variant	Effect	Δscore
22:28987070:TCCTA:T	acceptor_loss	1.0000
22:28987071:CCTA:C	acceptor_loss	1.0000
22:28987072:CTAGA:C	acceptor_loss	1.0000
22:28987073:TA:T	acceptor_loss	1.0000
22:28987074:A:AG	acceptor_gain	1.0000
22:28987074:A:AT	acceptor_loss	1.0000
22:28987074:AGAT:A	acceptor_gain	1.0000
22:28987075:G:GC	acceptor_gain	1.0000
22:28987075:GA:G	acceptor_gain	1.0000
22:28987075:GAT:G	acceptor_gain	1.0000
22:28987075:GATG:G	acceptor_gain	1.0000
22:28987075:GATGC:G	acceptor_gain	1.0000
22:28987197:GCAAG:G	donor_gain	1.0000
22:28987202:G:GC	donor_loss	1.0000
22:28987202:G:GG	donor_gain	1.0000
22:28987203:T:A	donor_loss	1.0000
22:29042569:GGT:G	donor_loss	1.0000
22:29042570:G:C	donor_loss	1.0000
22:29042571:T:A	donor_loss	1.0000
22:29043297:A:AG	acceptor_gain	1.0000
22:29043297:AGCT:A	acceptor_gain	1.0000
22:29043298:G:GT	acceptor_gain	1.0000
22:29043298:GC:G	acceptor_gain	1.0000
22:29043298:GCT:G	acceptor_gain	1.0000
22:29043298:GCTG:G	acceptor_gain	1.0000
22:29043298:GCTGA:G	acceptor_gain	1.0000
22:29043392:A:T	donor_gain	1.0000
22:29043409:G:GT	donor_gain	1.0000
22:29043427:TCGA:T	donor_gain	1.0000
22:29043428:CGAGT:C	donor_loss	1.0000

AlphaMissense

6076 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:28884008:T:C	L81P	1.000
22:28884019:T:C	F85L	1.000
22:28884020:T:C	F85S	1.000
22:28884020:T:G	F85C	1.000
22:28884021:C:A	F85L	1.000
22:28884021:C:G	F85L	1.000
22:28884031:G:A	G89R	1.000
22:28884031:G:C	G89R	1.000
22:28884031:G:T	G89W	1.000
22:28884047:C:A	A94D	1.000
22:28884052:G:A	G96S	1.000
22:28884052:G:C	G96R	1.000
22:28884052:G:T	G96C	1.000
22:28884053:G:A	G96D	1.000
22:28884053:G:T	G96V	1.000
22:28884059:T:A	I98N	1.000
22:28987080:A:G	H102R	1.000
22:28987081:C:A	H102Q	1.000
22:28987081:C:G	H102Q	1.000
22:28987092:T:C	L106P	1.000
22:28987094:T:A	C107S	1.000
22:28987094:T:C	C107R	1.000
22:28987095:G:A	C107Y	1.000
22:28987095:G:C	C107S	1.000
22:28987095:G:T	C107F	1.000
22:28987096:T:G	C107W	1.000
22:28987133:T:A	W120R	1.000
22:28987133:T:C	W120R	1.000
22:28987135:G:C	W120C	1.000
22:28987135:G:T	W120C	1.000

dbSNP variants (sampled 300 via entrez): RS1000004119 (22:29015959 T>C), RS1000005096 (22:28900704 G>A), RS1000010206 (22:28951501 G>A), RS1000015607 (22:28994863 G>A), RS1000061703 (22:29038687 T>C), RS1000062780 (22:28951813 G>A), RS1000066527 (22:28994522 C>T), RS1000071072 (22:28978833 A>T), RS1000082083 (22:29031001 C>A,G,T), RS1000086026 (22:28988749 C>T), RS1000098236 (22:28899390 T>G), RS1000143793 (22:28917443 A>C,G), RS1000183495 (22:29039439 A>G), RS1000198809 (22:28933450 C>T), RS1000210387 (22:28997272 A>C)

Disease associations

OMIM: gene MIM:612062 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (1): complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000080	Abnormality of reproductive system physiology
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0000859	Increased circulating aldosterone concentration
HP:0000975	Hyperhidrosis
HP:0000998	Hypertrichosis
HP:0001065	Striae distensae
HP:0001324	Muscle weakness
HP:0001824	Weight loss
HP:0001939	Abnormality of metabolism/homeostasis
HP:0001962	Palpitations
HP:0002027	Abdominal pain
HP:0002900	Hypokalemia
HP:0003110	Abnormality of urine homeostasis
HP:0003118	Increased circulating cortisol level
HP:0003466	Paradoxical increased cortisol secretion on dexamethasone suppression test
HP:0004324	Increased body weight
HP:0006744	Adrenocortical carcinoma
HP:0011748	Adrenocorticotropic hormone deficiency
HP:0012030	Increased urinary cortisol level
HP:0025134	Increased serum estradiol
HP:0025269	Panic attack
HP:0025380	Increased circulating androstenedione concentration
HP:0025436	Elevated serum 11-deoxycortisol
HP:0030078	Lung adenocarcinoma
HP:0030348	Increased circulating androgen concentration
HP:0500022	Abnormal circulating dehydroepiandrosterone concentration

GWAS associations

71 associations (top):

Study	Trait	p-value
GCST000829_15	Waist-hip ratio	1.000000e-11
GCST002553_2	Pancreatic cancer	1.000000e-08
GCST002782_199	Waist-to-hip ratio adjusted for body mass index	7.000000e-10
GCST002782_200	Waist-to-hip ratio adjusted for body mass index	2.000000e-06
GCST002782_201	Waist-to-hip ratio adjusted for body mass index	7.000000e-13
GCST002782_202	Waist-to-hip ratio adjusted for body mass index	7.000000e-06
GCST002782_203	Waist-to-hip ratio adjusted for body mass index	4.000000e-09
GCST002782_204	Waist-to-hip ratio adjusted for body mass index	6.000000e-12
GCST003855_1	Gut microbiota (bacterial taxa)	3.000000e-06
GCST004063_49	Waist circumference adjusted for body mass index	4.000000e-09
GCST004063_61	Waist circumference adjusted for body mass index	3.000000e-08
GCST004064_41	Waist-hip ratio	1.000000e-08
GCST004064_78	Waist-hip ratio	1.000000e-09
GCST004505_5	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	8.000000e-09
GCST004505_6	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	3.000000e-06
GCST004567_111	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	6.000000e-09
GCST004567_125	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	1.000000e-13
GCST004567_133	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	2.000000e-06
GCST004567_16	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	8.000000e-09
GCST004567_34	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	1.000000e-13
GCST004567_52	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	2.000000e-06
GCST004576_60	Waist-to-hip ratio adjusted for body mass index	1.000000e-09
GCST004576_61	Waist-to-hip ratio adjusted for body mass index	1.000000e-09
GCST004576_62	Waist-to-hip ratio adjusted for body mass index	3.000000e-07
GCST004576_63	Waist-to-hip ratio adjusted for body mass index	4.000000e-06
GCST004576_64	Waist-to-hip ratio adjusted for body mass index	4.000000e-14
GCST004576_65	Waist-to-hip ratio adjusted for body mass index	5.000000e-13
GCST004578_101	Waist-to-hip ratio adjusted for BMI in active individuals	2.000000e-10
GCST004578_136	Waist-to-hip ratio adjusted for BMI in active individuals	1.000000e-06
GCST004578_143	Waist-to-hip ratio adjusted for BMI in active individuals	5.000000e-06

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0004343	waist-hip ratio
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007874	gut microbiome measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0006340	mean arterial pressure
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009270	heel bone mineral density
EFO:0004348	hematocrit
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004533	alkaline phosphatase measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2269577	XBP1, ZNRF3	3	2.00	1	Platinum compounds

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	5
Valproic Acid	affects expression, decreases methylation, increases expression	4
bisphenol A	decreases methylation, affects cotreatment, increases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
benzo(e)pyrene	decreases methylation, increases methylation	1
versicolorin A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Zoledronic Acid	decreases expression	1
Arsenic Trioxide	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1
Dexamethasone	increases expression, affects cotreatment	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8DL	Ubigene A-549 ZNRF3 KO	Cancer cell line	Male
CVCL_TZ55	HAP1 ZNRF3 (-) 1	Cancer cell line	Male
CVCL_XV36	HAP1 ZNRF3 (-) 2	Cancer cell line	Male
CVCL_XV37	HAP1 ZNRF3 (-) 3	Cancer cell line	Male
CVCL_XV38	HAP1 ZNRF3 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder