RNF43

Chr 17AD

ring finger protein 43

Also known as: RNF124, SSPCS, URCC

NCBI Gene: 54894ENSG00000108375UniProt: Q68DV7

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. [provided by RefSeq, Mar 2015]

Primary Disease Associations & Inheritance

Sessile serrated polyposis cancer syndromeMIM #617108
AD
1
Active trials
30
Pathogenic / LP
481
ClinVar variants
8
Pubs (1 yr)
1.9
Missense Z
0.37
LOEUF
Clinical Summary— RNF43
🧬
Gene-Disease Validity (ClinGen)
sessile serrated polyposis cancer syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.73) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
30 Pathogenic / Likely Pathogenic· 302 VUS of 481 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
📖
GeneReview available — RNF43
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.37LOEUF
pLI 0.735
Z-score 4.40
OE 0.20 (0.11–0.37)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.85Z-score
OE missense 0.75 (0.69–0.82)
339 obs / 449.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.11–0.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.69–0.82)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 7 / 35.1Missense obs/exp: 339 / 449.5Syn Z: 1.08

ClinVar Variant Classifications

481 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic6
VUS302
Likely Benign140
Conflicting9
24
Pathogenic
6
Likely Pathogenic
302
VUS
140
Likely Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
12
0
24
Likely Pathogenic
5
0
1
0
6
VUS
5
284
11
2
302
Likely Benign
0
7
24
109
140
Benign
0
0
0
0
0
Conflicting
—9
Total2229148111481

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RNF43 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Sessile serrated polyposis cancer syndrome

MIM #617108

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer.
Yaeger R et al.·Cancer Cell
2018
Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test?
Rebuzzi F et al.·Int J Mol Sci
2023Review
Charting co-mutation patterns associated with actionable drivers in intrahepatic cholangiocarcinoma.
Kendre G et al.·J Hepatol
2023
RNF43 in cancer: Molecular understanding and clinical significance in immunotherapy.
Huo X et al.·J Gene Med
2024Review
Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome.
Brinch HH et al.·Fam Cancer
2024Cohort
MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance.
White M et al.·Nature
2026
Assessing genotype-phenotype correlations in colorectal cancer with deep learning: a multicentre cohort study.
Gustav M et al.·Lancet Digit Health
2025Cohort
RNF43 pathogenic Germline variant in a family with colorectal cancer.
Mikaeel RR et al.·Clin Genet
2022
Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer.
Karamitopoulou E et al.·Gut
2023
Genomic landscape of colorectal carcinogenesis.
Kim JC et al.·J Cancer Res Clin Oncol
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
PRICKLE3 protects VANGL proteins from CK1-mediated phosphorylation and RNF43-mediated degradation.
Radaszkiewicz KA et al.·Commun Biol
2025Open Access
Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis.
Palles C et al.·Gut
2025Functional
Bioinformatic Analysis of RNF43 and Its Co-expressors As Prognostic Biomarkers for Gastric Cancer.
Tsubaki M et al.·Cureus
2025Open Access
Brd4 BD1 Domain Antagonism of MS436 Preserves Blood-Brain Barrier Integrity via Rnf43/β-Catenin Signaling Pathway.
Li C et al.·Adv Sci (Weinh)
2026Open Access
STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency.
He Z et al.·Cell Chem Biol
2025
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps
van Herwaarden YJ et al.·Histopathology
2021
RNF43 and PWWP2B inhibit cancer cell proliferation and are predictive or prognostic biomarker for FDA-approved drugs in patients with advanced gastric cancer
Sohn SH et al.·J Cancer
2021Cohort
Rnf43 is "lord of the ring" finger proteins in remyelination.
Sardar D et al.·Neuron
2021
RNF43 and ZNRF3 in Wnt Signaling - A Master Regulator at the Membrane
Farnhammer F et al.·Int J Stem Cells
2023
Oncogenic fusion transcript analysis identified ADAP1-NOC4L, potentially associated with metastatic colorectal cancer
Talebi A et al.·Cancer Med
2023
The tumor biological significance of RNF43 and LRP1B in gastric cancer is complex and context-dependent
Holm B et al.·Sci Rep
2023
Clinical and Molecular Profiling of Colorectal Cancer: A Comprehensive Cohort Study of BRAF-Mutated Cases from a Tertiary Centre
Freckelton J et al.·Curr Oncol
2025Cohort
New Target(s) for RNF43 Regulation: Implications for Therapeutic Strategies
Nag JK et al.·Int J Mol Sci
2024
Issues with RNF43 antibodies to reliably detect intracellular location
Li S et al.·PLoS One
2023
Top 9 full-text resultsSearch PubTator3 ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients