Sessile serrated polyposis cancer syndrome

Summary

Sessile serrated polyposis cancer syndrome (MONDO:0014919) is a cancer caused by RNF43 (GenCC Definitive), with 1 cohort gene (1 CIViC-evidence somatic driver; 253 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: RNF43 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 253

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sessile serrated polyposis cancer syndrome
Mondo ID	MONDO:0014919
OMIM	617108
UMLS	C4310714
MedGen	934681
GARD	0025033
Is cancer (heuristic)	yes

Also known as: sessile serrated polyposis cancer syndrome · sessile serrated polyposis cancer syndrome; SSPCS · SSPCS

Data availability: 253 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hyperplastic polyposis syndrome › sessile serrated polyposis cancer syndrome

Related subtypes (1): colon serrated polyposis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

253 retrieved; paginated sample, class counts are floors:

156 uncertain significance, 53 conflicting classifications of pathogenicity, 22 pathogenic, 10 benign/likely benign, 7 likely pathogenic, 3 likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
190226	NM_017763.6(RNF43):c.394C>T (p.Arg132Ter)	RNF43	Pathogenic	criteria provided, single submitter
3066259	NM_017763.6(RNF43):c.1995del (p.Gly666fs)	RNF43	Pathogenic	criteria provided, single submitter
3392562	NM_017763.6(RNF43):c.256del (p.His86fs)	RNF43	Pathogenic	criteria provided, single submitter
4539774	NM_017763.6(RNF43):c.349dup (p.Arg117fs)	RNF43	Pathogenic	criteria provided, single submitter
4812945	NM_017763.6(RNF43):c.1207_1210dup (p.Arg404fs)	RNF43	Pathogenic	criteria provided, single submitter
4812946	NM_017763.6(RNF43):c.1617dup (p.Gly540fs)	RNF43	Pathogenic	criteria provided, single submitter
4812947	NM_017763.6(RNF43):c.1691G>A (p.Trp564Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812948	NM_017763.6(RNF43):c.1383del (p.Pro462fs)	RNF43	Pathogenic	criteria provided, single submitter
4812949	NM_017763.6(RNF43):c.127G>T (p.Glu43Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812950	NM_017763.6(RNF43):c.697C>T (p.Gln233Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812951	NM_017763.6(RNF43):c.1650C>A (p.Tyr550Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812954	NM_017763.6(RNF43):c.1840C>T (p.Gln614Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812955	NM_017763.6(RNF43):c.1016_1017del (p.Leu339fs)	RNF43	Pathogenic	criteria provided, single submitter
4812956	NM_017763.6(RNF43):c.1403C>G (p.Ser468Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812958	NM_017763.6(RNF43):c.997C>T (p.Gln333Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812960	NM_017763.6(RNF43):c.1434_1435insTCCAGTGTCT (p.Val479fs)	RNF43	Pathogenic	criteria provided, single submitter
4812961	NM_017763.6(RNF43):c.724C>T (p.Gln242Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812963	NM_017763.6(RNF43):c.64C>T (p.Gln22Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812964	NM_017763.6(RNF43):c.1308_1449del (p.Arg437fs)	RNF43	Pathogenic	criteria provided, single submitter
4812965	NM_017763.6(RNF43):c.1252_1255dup (p.Ser419fs)	RNF43	Pathogenic	criteria provided, single submitter
4812966	NM_017763.6(RNF43):c.913C>T (p.Gln305Ter)	RNF43	Pathogenic	criteria provided, single submitter
4812968	NM_017763.6(RNF43):c.1433_1434del (p.Ser478fs)	RNF43	Pathogenic	criteria provided, single submitter
1801831	NM_017763.6(RNF43):c.2308+1G>T	RNF43	Likely pathogenic	no assertion criteria provided
3065449	NM_017763.6(RNF43):c.1530C>A (p.Tyr510Ter)	RNF43	Likely pathogenic	criteria provided, single submitter
4812952	NM_017763.6(RNF43):c.582+1G>C	RNF43	Likely pathogenic	criteria provided, single submitter
4812957	NM_017763.6(RNF43):c.253-2A>C	RNF43	Likely pathogenic	criteria provided, single submitter
4812959	NM_017763.6(RNF43):c.2308+1G>A	RNF43	Likely pathogenic	criteria provided, single submitter
4812967	NM_017763.6(RNF43):c.1969dup (p.Arg657fs)	RNF43	Likely pathogenic	criteria provided, single submitter
4813021	NM_017763.6(RNF43):c.582+1G>A	RNF43	Likely pathogenic	criteria provided, single submitter
1004115	NM_017763.6(RNF43):c.1642G>A (p.Val548Ile)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
RNF43	LoF	CHOL,COAD,COADREAD,ESCA,LUSC,OVT,PAAD,PANCREAS,PRAD,PROSTATE,STAD,UCEC

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RNF43	Definitive	Autosomal dominant	sessile serrated polyposis cancer syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNF43	Orphanet:157798	Serrated polyposis syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNF43	HGNC:18505	ENSG00000108375	Q68DV7	E3 ubiquitin-protein ligase RNF43	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNF43	E3 ubiquitin-protein ligase RNF43	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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNF43	Transcription factor	no	2.3.2.27	Znf_RING, Znf_RING/FYVE/PHD, ZNRF-3_ecto

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
gingival epithelium	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNF43	202	broad	marker	cervix squamous epithelium, rectum, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNF43	1,991

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNF43	Q68DV7	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by RNF43 mutants	1	1268.9×	0.005	RNF43
Signaling by WNT in cancer	1	601.0×	0.005	RNF43
Regulation of FZD by ubiquitination	1	519.1×	0.005	RNF43
TCF dependent signaling in response to WNT	1	117.7×	0.014	RNF43
Signaling by WNT	1	112.0×	0.014	RNF43
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	RNF43
Disease	1	13.1×	0.087	RNF43
Signal Transduction	1	10.2×	0.098	RNF43

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Wnt receptor catabolic process	1	8426.0×	7e-04	RNF43
negative regulation of Wnt signaling pathway	1	343.9×	0.006	RNF43
stem cell proliferation	1	312.1×	0.006	RNF43
Wnt signaling pathway	1	99.7×	0.015	RNF43
ubiquitin-dependent protein catabolic process	1	74.2×	0.016	RNF43
protein ubiquitination	1	41.4×	0.024	RNF43

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNF43	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNF43	2.3.2.27	RING-type E3 ubiquitin transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

0 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RNF43

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RNF43	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.