RNF43

Summary

RNF43 (ring finger protein 43, HGNC:18505) is a protein-coding gene on chromosome 17q22, encoding E3 ubiquitin-protein ligase RNF43 (Q68DV7). E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination, endocytosis and subsequent degradation of Wnt receptor complex components Frizzled.

The protein encoded by this gene is a RING-type E3 ubiquitin ligase and is predicted to contain a transmembrane domain, a protease-associated domain, an ectodomain, and a cytoplasmic RING domain. This protein is thought to negatively regulate Wnt signaling, and expression of this gene results in an increase in ubiquitination of frizzled receptors, an alteration in their subcellular distribution, resulting in reduced surface levels of these receptors. Mutations in this gene have been reported in multiple tumor cells, including colorectal and endometrial cancers. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 54894 — RefSeq curated summary.

At a glance

• Gene–disease (curated): sessile serrated polyposis cancer syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 1,366 total — 23 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 16
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 12 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency emerging evidence, triplosensitivity no evidence
• MANE Select transcript: NM_017763

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18505
Approved symbol	RNF43
Name	ring finger protein 43
Location	17q22
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20315, RNF124, DKFZp781H0392, URCC
Ensembl gene	ENSG00000108375
Ensembl biotype	protein_coding
OMIM	612482
Entrez	54894

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000407977, ENST00000577625, ENST00000577716, ENST00000580014, ENST00000581868, ENST00000582293, ENST00000583753, ENST00000584437, ENST00000876688, ENST00000876690

RefSeq mRNA: 3 — MANE Select: NM_017763 NM_001305544, NM_001305545, NM_017763

CCDS: CCDS11607, CCDS82172

Canonical transcript exons

ENST00000407977 — 10 exons

Exon	Start	End
ENSE00000739457	58360149	58360251
ENSE00000739458	58360783	58360944
ENSE00000739460	58362544	58362648
ENSE00000739461	58363275	58363406
ENSE00000820280	58357468	58358823
ENSE00001553129	58415326	58415962
ENSE00002691663	58353676	58354986
ENSE00002727513	58417017	58417534
ENSE00003574371	58363526	58363600
ENSE00003584277	58370911	58371033

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 88.57.

FANTOM5 (CAGE): breadth broad, TPM avg 5.2106 / max 412.8921, expressed in 609 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167263	2.1801	465
167264	1.9017	480
167262	0.3426	171
167261	0.2654	119
167267	0.1360	62
167254	0.0903	24
167265	0.0870	42
167266	0.0637	23
167258	0.0371	16
167257	0.0238	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	88.57	silver quality
rectum	UBERON:0001052	88.00	gold quality
gingival epithelium	UBERON:0001949	87.61	silver quality
squamous epithelium	UBERON:0006914	86.86	silver quality
esophagus squamous epithelium	UBERON:0006920	86.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.50	gold quality
colonic mucosa	UBERON:0000317	85.29	gold quality
epithelium of esophagus	UBERON:0001976	85.28	gold quality
mucosa of transverse colon	UBERON:0004991	85.14	gold quality
duodenum	UBERON:0002114	84.50	gold quality
tongue squamous epithelium	UBERON:0006919	84.45	gold quality
gingiva	UBERON:0001828	84.37	silver quality
parotid gland	UBERON:0001831	84.17	gold quality
lower esophagus mucosa	UBERON:0035834	82.99	gold quality
jejunal mucosa	UBERON:0000399	82.68	gold quality
colonic epithelium	UBERON:0000397	82.33	gold quality
right adrenal gland cortex	UBERON:0035827	81.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.61	gold quality
right adrenal gland	UBERON:0001233	81.57	gold quality
hair follicle	UBERON:0002073	81.40	gold quality
epithelial cell of pancreas	CL:0000083	80.56	silver quality
right uterine tube	UBERON:0001302	80.56	gold quality
left adrenal gland cortex	UBERON:0035825	80.37	gold quality
left adrenal gland	UBERON:0001234	79.99	gold quality
epithelium of bronchus	UBERON:0002031	79.98	gold quality
adrenal cortex	UBERON:0001235	79.89	gold quality
epithelium of nasopharynx	UBERON:0001951	79.82	silver quality
adrenal gland	UBERON:0002369	79.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.47	silver quality
bronchus	UBERON:0002185	79.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.05

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting RNF43, 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-1277-5P	100.00	73.95	5056
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728

Functional genomics

ClinGen dosage: haploinsufficiency 2 (emerging evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• RNF43 may exert its growth promoting effect in an antocrine manner and may be a novel diagnostic marker for colorectal cancer (PMID:15492824)
• These results infer that RNF43 is a resident protein of the ER and, at least partially, the nuclear membrane, with ubiquitin ligase activity and may be involved in cell growth control potentially through the interaction with HAP95. (PMID:18313049)
• These findings suggest that RNF43 is associated with p53-mediated apoptosis in collaboration with NEDL1 in colorectal carcinogenesis. (PMID:21108931)
• RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation (PMID:22895187)
• RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. (PMID:23096461)
• RNF43 is involved in tumorigenesis and progression of human hepatocellular carcinoma. (PMID:23136185)
• mutational inactivation of RNF43 in pancreatic adenocarcinoma confers Wnt dependency (PMID:23847203)
• RNF43 mutations are recurrent in Chinese patients with mucinous ovarian carcinoma but absent in other subtypes of ovarian cancer. (PMID:24001777)
• 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)
• These results indicate that RNF43 mutation might cause downregulation of the expression of ring finger protein 43 and play a crucial role during development of intraductal papillary mucinous neoplasm of the pancreas. (PMID:25081753)
• RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers (PMID:25344691)
• we found that the decreased expression of RNF43 in glioma was associated with poor prognosis by the Kaplan-Meier survival analysis. Importantly, multivariate analysis suggested RN43 as an independent predictor of overall survival. (PMID:25755738)
• Missense mutations of RNF43 change their localization from the endosome to the endoplasmic reticulum. (PMID:25825523)
• 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)
• Authors also identified ring finger 43 (RNF43), an inhibitor of Wnt/beta-catenin signaling, as a target of miR-550a-5p. (PMID:25961913)
• The nucleoprotein of influenza A virus targets RNF43 to modulate p53 ubiquitination levels and hence causes p53 stabilization which is conducive to an enhanced apoptosis level in the host cells. (PMID:25996295)
• RNF43 might act as a tumor suppressor in gastric carcinoma and might be a potential indicator for the clinical assessment of gastric cancer prognosis (PMID:26184844)
• RNF43 gene harbored not only exceedingly high mutations but also mutational intratumoral heterogeneity, which together might play a role in tumorigenesis of gastric and colorectal cancers. (PMID:26297255)
• RNF43 inhibits the Wnt pathway downstream of oncogenic mutations that activate the pathway. (PMID:26350900)
• our study exhibited the expression patterns and correlation of RNF43 and p53 pathway proteins involved in cell cycling (PMID:26823834)
• PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of traditional serrated adenomas (TSAs). (PMID:26924569)
• RNF43 is down-regulated in intrahepatic cholangiocarcinoma and may play a crucial role during development of ICC. (PMID:26980022)
• The finding of RNF43 mutation in sessile serrated adenoma and traditional serrated adenoma, but not in tubulovillous/villous adenoma, indicated that RNF43 mutation is an early and specific molecular aberration in the serrated colorectal carcinoma pathway. (PMID:27305845)
• RNF43 mutation constitutes an important mutated driver gene for the Serrated Neoplasia pathway in both the sporadic and familial Polyposis settings. (PMID:27329244)
• Chimeric transcript resulting from the fusion of RNF43 and SUPT4H1 was found to occur frequently in primary colorectal carcinoma. (PMID:27461012)
• Mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. (PMID:27514024)
• 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)
• The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic microsatellite unstable colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. (PMID:28573495)
• Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer. (PMID:29756208)
• 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)
• RNF43 frameshift mutations were related to distant metastasis and TNM-stage in an MS status-dependent manner, but they contributed to tumourigenesis in right-sided colon cancer independent of MS status (PMID:31122752)
• The study found that an SNP (rs2257205) of the RNF43 X117 site was associated with overall survival in a Chinese Colorectal Cancer Cohort. (PMID:31140864)
• The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis. (PMID:31811196)
• Commonly observed RNF43 mutations retain functionality in attenuating Wnt/beta-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers. (PMID:32103169)
• RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer. (PMID:32236609)
• Protease associated domain of RNF43 is not necessary for the suppression of Wnt/beta-catenin signaling in human cells. (PMID:32527265)
• A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis. (PMID:32934222)
• RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. (PMID:32965059)
• The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition. (PMID:33067269)
• RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps. (PMID:33098683)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rnf43	ENSMUSG00000034177
rattus_norvegicus	Rnf43	ENSRNOG00000007606

Paralogs (1): ZNRF3 (ENSG00000183579)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF43 — Q68DV7 (reviewed: Q68DV7)

Alternative names: RING finger protein 43, RING-type E3 ubiquitin transferase RNF43

All UniProt accessions (2): Q68DV7, J3KSE3

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, endocytosis and subsequent degradation of Wnt receptor complex components Frizzled. Acts on both canonical and non-canonical Wnt signaling pathway. Along with RSPO2 and ZNRF3, constitutes a master switch that governs limb specification.

Subunit / interactions. Interacts with AKAP8L, NONO and SFPQ. Interacts with FZD5. Identified in a complex composed of RNF43, LGR5 and RSPO1. Interacts with RSPO2. Interacts with LMBR1L.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Nucleus envelope.

Tissue specificity. Expressed in fetal kidney, fetal lung, in colon cancer tissues, hepatocellular carcinomas and lung adenocarcinomas. Overexpressed in colorectal cancer cell lines.

Post-translational modifications. Autoubiquitinated.

Disease relevance. Sessile serrated polyposis cancer syndrome (SSPCS) [MIM:617108] A rare disease characterized by multiple and/or large serrated polyps developing in the colon, and an increased personal and familial risk of colorectal cancer. A patient is diagnosed with SSPCS if at least one of the following criteria is met: the presence of at least five sessile serrated polyps proximal to the sigmoid colon, two of which are greater than 10 mm in diameter; the presence of any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis; the presence of more than 20 serrated polyps of any size distributed throughout the colon. Sessile serrated polyps are also known as sessile serrated adenomas (SSA) and are estimated to be responsible for 20 to 35% of all colon cancers. Individuals with SSPCS may have a strong personal or family history of extracolonic cancers. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Acts as a cytotoxic T-lymphocyte tumor antigen, suggesting that it may be used as a target for cancer immunotherapy.

Similarity. Belongs to the ZNRF3 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q68DV7-1	1	yes
Q68DV7-2	2
Q68DV7-3	3
Q68DV7-4	4

RefSeq proteins (3): NP_001292473, NP_001292474, NP_060233* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR040700	ZNRF-3_ecto	Domain
IPR045907	RNF43_Znf_RING	Domain
IPR051073	ZNRF3_Arkadia_E3_ligases	Family

Pfam: PF13639, PF18212

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (54 total): strand 11, sequence variant 7, compositionally biased region 6, mutagenesis site 4, sequence conflict 4, helix 4, region of interest 4, splice variant 3, glycosylation site 2, topological domain 2, turn 2, signal peptide 1, chain 1, disulfide bond 1, transmembrane region 1, zinc finger region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4KNG	X-RAY DIFFRACTION	2.5
8WVU	ELECTRON MICROSCOPY	3.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q68DV7-F1	55.86	0.15

Functional residue map

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

Disulfide bonds (1): 91–119

Glycosylation sites (2): 62, 92

Mutagenesis-validated functional residues (4):

Position	Phenotype
290	dominant-negative mutant, loss of e3 ligase activity and activation of the wnt signaling pathway; when associated with s
292	dominant-negative mutant, loss of e3 ligase activity and activation of the wnt signaling pathway; when associated with s
295	dominant-negative mutant, loss of e3 ligase activity and activation of the wnt signaling pathway; when associated with s
298	dominant-negative mutant, loss of e3 ligase activity and activation of the wnt signaling pathway; when associated with s

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-4641263	Regulation of FZD by ubiquitination
R-HSA-5340588	Signaling by RNF43 mutants
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-4791275	Signaling by WNT in cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers

MSigDB gene sets: 268 (showing top): RNGTGGGC_UNKNOWN, CREL_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOZGIT_ESR1_TARGETS_DN, AAGCCAT_MIR135A_MIR135B, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, RACCACAR_AML_Q6, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, USF_C, CHANDRAN_METASTASIS_DN, GOBP_STEM_CELL_PROLIFERATION, AGGCACT_MIR5153P, NFKB_Q6, PATIL_LIVER_CANCER, NKX61_01

GO Biological Process (6): ubiquitin-dependent protein catabolic process (GO:0006511), Wnt signaling pathway (GO:0016055), protein ubiquitination (GO:0016567), negative regulation of Wnt signaling pathway (GO:0030178), Wnt receptor catabolic process (GO:0038018), stem cell proliferation (GO:0072089)

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 (6): nuclear envelope (GO:0005635), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1
Signaling by WNT in cancer	1
Signal Transduction	1
Signaling by WNT	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	2
intracellular membrane-bounded organelle	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell surface receptor signaling pathway	1
protein modification by small protein conjugation	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
negative regulation of Wnt signaling pathway	1
receptor catabolic process	1
cell population proliferation	1
stem cell division	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
nucleus	1
organelle envelope	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1462 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF43	LGR4	Q9BXB1	986
RNF43	RSPO1	Q2MKA7	981
RNF43	LGR5	O75473	949
RNF43	AKAP8L	Q9ULX6	934
RNF43	RSPO2	Q6UXX9	877
RNF43	AXIN2	Q9Y2T1	787
RNF43	LRP5	O75197	773
RNF43	ZNRF3	Q9ULT6	759
RNF43	RSPO4	Q2I0M5	705
RNF43	DVL1	O14640	705
RNF43	CDKN2A	P42771	700
RNF43	RSPO3	Q9BXY4	698
RNF43	GNAS	Q5JWF2	698
RNF43	FZD5	Q13467	697
RNF43	KRAS	P01116	670

IntAct

37 interactions, top by confidence:

A	B	Type	Score
RNF43	UBE2D2	psi-mi:“MI:0220”(ubiquitination reaction)	0.590
RNF43	UBE2D3	psi-mi:“MI:0220”(ubiquitination reaction)	0.590
UBE2D2	RNF43	psi-mi:“MI:0915”(physical association)	0.590
RNF43	UBE2D3	psi-mi:“MI:0915”(physical association)	0.590
RNF43	SFPQ	psi-mi:“MI:0915”(physical association)	0.560
RNF43	SFPQ	psi-mi:“MI:0403”(colocalization)	0.560
RNF43	NONO	psi-mi:“MI:0403”(colocalization)	0.560
RNF43	AKAP8L	psi-mi:“MI:0915”(physical association)	0.510
RNF43	MYADM	psi-mi:“MI:0915”(physical association)	0.500
UBB	RNF43	psi-mi:“MI:0915”(physical association)	0.400
RNF43	UBB	psi-mi:“MI:0915”(physical association)	0.400
UBE2D1	RNF43	psi-mi:“MI:0915”(physical association)	0.370
RNF43	UBE2D4	psi-mi:“MI:0915”(physical association)	0.370
RNF43	UBE2E1	psi-mi:“MI:0915”(physical association)	0.370
RNF43	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370
UBE2N	RNF43	psi-mi:“MI:0915”(physical association)	0.370
RNF43	CSNK1E	psi-mi:“MI:0914”(association)	0.350
SLC9A5	NBAS	psi-mi:“MI:0914”(association)	0.350
AKT1	RNF43	psi-mi:“MI:2364”(proximity)	0.270
BRAF	RNF43	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	RNF43	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	RNF43	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (492): RNF43 (Biochemical Activity), UBE2D2 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), DVL2 (Affinity Capture-Western), RNF43 (Affinity Capture-Western), RNF43 (Co-localization), FZD5 (Affinity Capture-Western), RNF43 (Affinity Capture-Western), RNF43 (Affinity Capture-Western), RNF43 (Affinity Capture-Western), DVL2 (Affinity Capture-Western), MYADM (Affinity Capture-MS), CSNK1E (Affinity Capture-MS), CSNK2A1 (Affinity Capture-MS), RSPO2 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GU29, A6NLX4, A6QNY1, A9CBA0, B7ZWI3, O14669, O88472, P14784, P16297, P25918, P26896, Q0VFL4, Q13651, Q32M26, Q38J84, Q38J85, Q3SYS8, Q58CT8, Q5BK39, Q5EAA5, Q5HZE8, Q5NCP0, Q5RCL0, Q64322, Q68DV7, Q6AXS2, Q6AXU5, Q6NUJ2, Q6UWV7, Q86UW2, Q8BHB3, Q8BLR5, Q8BSU2, Q8C353, Q8C708, Q8K1T1, Q8MII8, Q8N6P7, Q8NET5, Q8R182

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

4 interactions.

A	Effect	B	Mechanism
RNF43	up-regulates	FZD2	relocalization
Ub:E2	“up-regulates activity”	RNF43	ubiquitination
RNF43	“down-regulates quantity by destabilization”	CDH1	ubiquitination
RNF43	“down-regulates quantity by destabilization”	TP53	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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
TICAM1, RIP1-mediated IKK complex recruitment	5	150.3×	5e-08
IKK complex recruitment mediated by RIP1	5	124.1×	7e-08
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	92.1×	1e-07
E3 ubiquitin ligases ubiquitinate target proteins	6	58.1×	8e-08
Downstream TCR signaling	5	32.1×	2e-05
Antigen processing: Ubiquitination & Proteasome degradation	9	16.7×	9e-08
Neddylation	5	11.8×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein K48-linked ubiquitination	6	46.0×	1e-06
protein polyubiquitination	6	31.5×	4e-06
ubiquitin-dependent protein catabolic process	5	16.9×	7e-04
protein ubiquitination	8	15.1×	4e-06
proteasome-mediated ubiquitin-dependent protein catabolic process	6	14.2×	2e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 12 cancer types — CHOL, COAD, COADREAD, ESCA, LUSC, OVT, PAAD, PANCREAS, PRAD, PROSTATE, STAD, UCEC.

Clinical variants and AI predictions

ClinVar

1366 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	9
Uncertain significance	798
Likely benign	391
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
190226	NM_017763.6(RNF43):c.394C>T (p.Arg132Ter)	Pathogenic
3026740	NM_017763.6(RNF43):c.295_296del (p.Leu99fs)	Pathogenic
3066259	NM_017763.6(RNF43):c.1995del (p.Gly666fs)	Pathogenic
3392562	NM_017763.6(RNF43):c.256del (p.His86fs)	Pathogenic
4539774	NM_017763.6(RNF43):c.349dup (p.Arg117fs)	Pathogenic
4812945	NM_017763.6(RNF43):c.1207_1210dup (p.Arg404fs)	Pathogenic
4812946	NM_017763.6(RNF43):c.1617dup (p.Gly540fs)	Pathogenic
4812947	NM_017763.6(RNF43):c.1691G>A (p.Trp564Ter)	Pathogenic
4812948	NM_017763.6(RNF43):c.1383del (p.Pro462fs)	Pathogenic
4812949	NM_017763.6(RNF43):c.127G>T (p.Glu43Ter)	Pathogenic
4812950	NM_017763.6(RNF43):c.697C>T (p.Gln233Ter)	Pathogenic
4812951	NM_017763.6(RNF43):c.1650C>A (p.Tyr550Ter)	Pathogenic
4812954	NM_017763.6(RNF43):c.1840C>T (p.Gln614Ter)	Pathogenic
4812955	NM_017763.6(RNF43):c.1016_1017del (p.Leu339fs)	Pathogenic
4812956	NM_017763.6(RNF43):c.1403C>G (p.Ser468Ter)	Pathogenic
4812958	NM_017763.6(RNF43):c.997C>T (p.Gln333Ter)	Pathogenic
4812960	NM_017763.6(RNF43):c.1434_1435insTCCAGTGTCT (p.Val479fs)	Pathogenic
4812961	NM_017763.6(RNF43):c.724C>T (p.Gln242Ter)	Pathogenic
4812963	NM_017763.6(RNF43):c.64C>T (p.Gln22Ter)	Pathogenic
4812964	NM_017763.6(RNF43):c.1308_1449del (p.Arg437fs)	Pathogenic
4812965	NM_017763.6(RNF43):c.1252_1255dup (p.Ser419fs)	Pathogenic
4812966	NM_017763.6(RNF43):c.913C>T (p.Gln305Ter)	Pathogenic
4812968	NM_017763.6(RNF43):c.1433_1434del (p.Ser478fs)	Pathogenic
1319731	NM_017763.6(RNF43):c.1976del (p.Gly659fs)	Likely pathogenic
1801831	NM_017763.6(RNF43):c.2308+1G>T	Likely pathogenic
2692006	NM_017763.6(RNF43):c.1009C>T (p.Arg337Ter)	Likely pathogenic
3065449	NM_017763.6(RNF43):c.1530C>A (p.Tyr510Ter)	Likely pathogenic
4812952	NM_017763.6(RNF43):c.582+1G>C	Likely pathogenic
4812957	NM_017763.6(RNF43):c.253-2A>C	Likely pathogenic
4812959	NM_017763.6(RNF43):c.2308+1G>A	Likely pathogenic

SpliceAI

1620 predictions. Top by Δscore:

Variant	Effect	Δscore
17:58360147:AC:A	donor_loss	1.0000
17:58360148:CCT:C	donor_loss	1.0000
17:58362542:A:AC	donor_gain	1.0000
17:58362543:C:CC	donor_gain	1.0000
17:58362645:CTGG:C	acceptor_gain	1.0000
17:58362649:C:CC	acceptor_gain	1.0000
17:58363269:GCTT:G	donor_loss	1.0000
17:58363270:CTTA:C	donor_loss	1.0000
17:58363271:TTA:T	donor_loss	1.0000
17:58363272:TACC:T	donor_loss	1.0000
17:58363404:CAG:C	acceptor_gain	1.0000
17:58363405:AGC:A	acceptor_loss	1.0000
17:58363406:GCTA:G	acceptor_loss	1.0000
17:58363407:C:CC	acceptor_gain	1.0000
17:58363407:CT:C	acceptor_loss	1.0000
17:58363601:C:CC	acceptor_gain	1.0000
17:58363602:T:C	acceptor_loss	1.0000
17:58363610:C:CT	acceptor_gain	1.0000
17:58370957:T:A	donor_gain	1.0000
17:58371029:TGGGA:T	acceptor_gain	1.0000
17:58371030:GGGA:G	acceptor_gain	1.0000
17:58371031:GGA:G	acceptor_gain	1.0000
17:58371031:GGAC:G	acceptor_loss	1.0000
17:58371032:GA:G	acceptor_gain	1.0000
17:58371033:ACT:A	acceptor_loss	1.0000
17:58371034:C:CC	acceptor_gain	1.0000
17:58371034:C:T	acceptor_loss	1.0000
17:58360249:CTC:C	acceptor_gain	0.9900
17:58360252:C:A	acceptor_loss	0.9900
17:58360252:C:CC	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002261 (17:58366857 AC>A), RS1000004714 (17:58399842 A>G), RS1000036188 (17:58415251 T>C,G), RS1000127164 (17:58386586 C>G), RS1000128619 (17:58410488 G>C), RS1000134083 (17:58384299 C>A), RS1000142712 (17:58363298 C>A,G,T), RS1000165279 (17:58377682 A>C,G), RS1000170977 (17:58403602 T>A,C), RS1000230560 (17:58370177 T>C), RS1000261509 (17:58418186 G>A), RS1000362133 (17:58381220 G>A), RS1000396079 (17:58396295 G>T), RS1000427330 (17:58396816 T>C), RS1000493165 (17:58409656 A>G,T)

Disease associations

OMIM: gene MIM:612482 | disease phenotypes: MIM:617108

GenCC curated gene-disease

Disease	Classification	Inheritance
sessile serrated polyposis cancer syndrome	Definitive	Autosomal dominant
hyperplastic polyposis syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
sessile serrated polyposis cancer syndrome	Definitive	AD

Mondo (4): sessile serrated polyposis cancer syndrome (MONDO:0014919), hyperplastic polyposis syndrome (MONDO:0015524), hereditary neoplastic syndrome (MONDO:0015356), colon serrated polyposis (MONDO:0100290)

Orphanet (2): Serrated polyposis syndrome (Orphanet:157798), Inherited cancer-predisposing syndrome (Orphanet:140162)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0002861	Melanoma
HP:0002862	Bladder carcinoma
HP:0003002	Breast carcinoma
HP:0005227	Adenomatous colonic polyposis
HP:0006725	Pancreatic adenocarcinoma
HP:0012125	Prostate cancer
HP:0012189	Hodgkin lymphoma
HP:0032222	Serrated intestinal polyps
HP:0100008	Schwannoma
HP:0100574	Biliary tract neoplasm
HP:0100615	Ovarian neoplasm
HP:0100728	Germ cell neoplasia
HP:0100808	Gastric diverticulum
HP:0100834	Neoplasm of the large intestine
HP:0200063	Colorectal polyposis

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000745_15	Pancreatic cancer	8.000000e-06
GCST001980_2	Circulating myeloperoxidase levels (plasma)	4.000000e-09
GCST002602_6	Vitamin D levels	1.000000e-06
GCST002774_29	Cognitive function	3.000000e-07
GCST004602_297	Mean corpuscular volume	2.000000e-11
GCST004630_219	Mean corpuscular hemoglobin	1.000000e-11
GCST006085_93	Prostate cancer	2.000000e-08
GCST010002_126	Refractive error	7.000000e-42
GCST010083_228	Hemoglobin levels	2.000000e-10
GCST011369_32	Iron status biomarkers (ferritin levels)	3.000000e-48
GCST90002390_120	Mean corpuscular hemoglobin	5.000000e-15
GCST90002392_22	Mean corpuscular volume	3.000000e-15

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005243	myeloperoxidase measurement
EFO:0004337	intelligence
EFO:0004527	mean corpuscular hemoglobin
EFO:0004509	hemoglobin measurement
EFO:0004459	ferritin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	3
Aflatoxin B1	increases methylation, affects expression, decreases expression, decreases methylation	3
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Estradiol	decreases expression	2
Quercetin	decreases expression, decreases phosphorylation	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
bisphenol A	affects expression	1
ethyl-p-hydroxybenzoate	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	decreases methylation, increases methylation	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	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
Oxaliplatin	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Methapyrilene	decreases methylation, increases methylation	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7IT	Ubigene 5637 RNF43 KO	Cancer cell line	Male
CVCL_D8GV	Ubigene HCA-7 RNF43 KO	Cancer cell line	Female
CVCL_E0MV	Ubigene HeLa RNF43 KO	Cancer cell line	Female
CVCL_F1YI	10170	Cancer cell line	Female
CVCL_TJ42	HAP1 RNF43 (-) 1	Cancer cell line	Male
CVCL_TJ43	HAP1 RNF43 (-) 2	Cancer cell line	Male
CVCL_TJ44	HAP1 RNF43 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04906343	Not specified	COMPLETED	Endoscopic Surveillance in Serrated Polyposis Syndrome and Low-risk of Advanced Neoplasia
NCT00001496	Not specified	COMPLETED	Establishment of Normal Breast Epithelial Cell Lines From Patients at High Risk for Breast Cancer
NCT00001898	Not specified	COMPLETED	Microarray Analysis for Human Genetic Disease
NCT00026884	Not specified	RECRUITING	Collection of Serum and Tissue Samples From Patients With Biopsy-Proved or Suspected Malignant Disease
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03160274	Not specified	RECRUITING	Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions
NCT03426878	Not specified	COMPLETED	Cancer Health Assessments Reaching Many
NCT03857594	Not specified	ACTIVE_NOT_RECRUITING	Integrative Sequencing In Germline and Hereditary Tumours
NCT03973450	Not specified	UNKNOWN	Epidemiology of Pituitary Tumours: Prevalence of Associated Neoplasia
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04261972	Not specified	ACTIVE_NOT_RECRUITING	Cell-free DNA in Hereditary And High-Risk Malignancies 1
NCT04494945	Not specified	RECRUITING	Identifying and Caring for Individuals With Inherited Cancer Syndrome
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04763915	Not specified	ACTIVE_NOT_RECRUITING	Improving Care After Inherited Cancer Testing
NCT05562778	Not specified	RECRUITING	Chatbot to Maximize Hereditary Cancer Genetic Risk Assessment
NCT05664867	Not specified	RECRUITING	Implementation of Population Cancer Genetic Services in Federally Qualified Health Centers (FQHC)
NCT05721326	Not specified	COMPLETED	Sequential EHR Based Interventions to Increase Genetic Testing for Breast and Ovarian Cancer Predisposition
NCT06096688	Not specified	RECRUITING	Discovering New Targets for Colorectal and Endometrial Cancer Risk Reduction
NCT06654466	Not specified	RECRUITING	Closing the GAPS: Guideline Adherence, Prevention and Surveillance in Hereditary Cancer
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06726642	Not specified	RECRUITING	CfDNA in Hereditary And High-risk Malignancies 2
NCT06914726	Not specified	ENROLLING_BY_INVITATION	Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes
NCT06927947	Not specified	RECRUITING	Navigation Interventions to Improve Cascade Genetic Testing Among Relatives of Patients With Hereditary Cancer Syndromes
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform
NCT07052266	Not specified	RECRUITING	Trial of Combined Obstetric Carrier Screening and Hereditary Cancer Screening
NCT07195071	Not specified	RECRUITING	Feasibility Trial of Combination of Obstetrical Carrier Screening and Hereditary Cancer Screening
NCT07378423	Not specified	RECRUITING	Questionnaire on Congenital Cancer Signs Through Self-Assessment
NCT07381985	Not specified	ENROLLING_BY_INVITATION	Strategy for Management of Patients With Hereditary Cancer Syndromes (HCS) in a Rural Environment
NCT07542405	Not specified	NOT_YET_RECRUITING	A Web-Based Program (Kindred) to Improve the Understanding of Genetic Cancer Risk and Cancer Genetic Testing in African American Families