Hyperplastic polyposis syndrome

Summary

Hyperplastic polyposis syndrome (MONDO:0015524) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Cohort genes: 1
• ClinVar variants: 33
• Phenotypes (HPO): 14
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1	Worldwide	Not yet validated
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0200063	Colorectal polyposis	Very frequent (80-99%)
HP:0005227	Adenomatous colonic polyposis	Frequent (30-79%)
HP:0100808	Gastric diverticulum	Frequent (30-79%)
HP:0100834	Neoplasm of the large intestine	Occasional (5-29%)
HP:0002861	Melanoma	Very rare (<1-4%)
HP:0002862	Bladder carcinoma	Very rare (<1-4%)
HP:0003002	Breast carcinoma	Very rare (<1-4%)
HP:0006725	Pancreatic adenocarcinoma	Very rare (<1-4%)
HP:0012125	Prostate cancer	Very rare (<1-4%)
HP:0012189	Hodgkin lymphoma	Very rare (<1-4%)
HP:0100008	Schwannoma	Very rare (<1-4%)
HP:0100574	Biliary tract neoplasm	Very rare (<1-4%)
HP:0100615	Ovarian neoplasm	Very rare (<1-4%)
HP:0100728	Germ cell neoplasia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperplastic polyposis syndrome
Mondo ID	MONDO:0015524
Orphanet	157798
ICD-11	1344352020
NCIT	C165469
SNOMED CT	763536006
UMLS	C4296896
MedGen	1645454
GARD	0016982
Is cancer (heuristic)	no

Also known as: serrated polyposis

Data availability: 33 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (30): benign digestive system neoplasm, autoimmune disorder of gastrointestinal tract, gastrointestinal mucositis, diarrheal disease, pancreas disorder, hepatobiliary disorder, digestive system cancer, peptic ulcer disease, stomach disorder, intestinal disorder, Meckel diverticulum, Cronkhite-Canada syndrome, diverticulosis, small-intestinal, diverticulosis of bowel, hernia, and retinal detachment, congenital enteropathy due to enteropeptidase deficiency, hereditary mixed polyposis syndrome, caudal duplication, Moyamoya disease with early-onset achalasia, thoraco-abdominal enteric duplication, digestive duplication, juvenile polyposis syndrome, umbilical cord ulceration-intestinal atresia syndrome, growth retardation-mild developmental delay-chronic hepatitis syndrome, common mesentery, neoplasm of oropharynx, gastrointestinal polyp, digestive system neuroendocrine neoplasm, digestive system infectious disorder, upper digestive tract disorder, congenital peritoneal encapsulation

Subtypes (2): sessile serrated polyposis cancer syndrome, 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

33 retrieved; paginated sample, class counts are floors:

14 conflicting classifications of pathogenicity, 11 uncertain significance, 4 benign/likely benign, 2 benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1110191	NM_017763.6(RNF43):c.1880T>C (p.Val627Ala)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1111196	NM_017763.6(RNF43):c.674G>A (p.Arg225His)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1140674	NM_017763.6(RNF43):c.1660C>T (p.Arg554Trp)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1165807	NM_017763.6(RNF43):c.1010G>A (p.Arg337Gln)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1166577	NM_017763.6(RNF43):c.1825C>T (p.Arg609Trp)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1166587	NM_017763.6(RNF43):c.2091C>T (p.His697=)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1167972	NM_017763.6(RNF43):c.575C>T (p.Pro192Leu)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1170669	NM_017763.6(RNF43):c.380G>A (p.Arg127Gln)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1502506	NM_017763.6(RNF43):c.1682G>A (p.Arg561Gln)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1586909	NM_017763.6(RNF43):c.811G>C (p.Val271Leu)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1599152	NM_017763.6(RNF43):c.792C>T (p.Ser264=)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
953189	NM_017763.6(RNF43):c.1211G>A (p.Arg404His)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
953598	NM_017763.6(RNF43):c.1114C>T (p.Pro372Ser)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
962308	NM_017763.6(RNF43):c.1969C>T (p.Arg657Trp)	RNF43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1415934	NM_017763.6(RNF43):c.1586G>A (p.Arg529Gln)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
1437324	NM_017763.6(RNF43):c.1604C>T (p.Ser535Leu)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
2692007	NM_017763.6(RNF43):c.783C>G (p.Asp261Glu)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
2885709	NM_017763.6(RNF43):c.2326GAG[1] (p.Glu777del)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
3780556	NM_017763.6(RNF43):c.1961G>A (p.Arg654Lys)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
3780557	NM_017763.6(RNF43):c.2097del (p.Ile700fs)	RNF43	Uncertain significance	criteria provided, single submitter
3780559	NM_017763.6(RNF43):c.2315A>C (p.Glu772Ala)	RNF43	Uncertain significance	criteria provided, single submitter
3780560	NM_017763.6(RNF43):c.260C>T (p.Pro87Leu)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
855229	NM_017763.6(RNF43):c.1705C>T (p.Pro569Ser)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
859220	NM_017763.6(RNF43):c.640C>G (p.Leu214Val)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
933701	NM_017763.6(RNF43):c.680G>A (p.Ser227Asn)	RNF43	Uncertain significance	criteria provided, multiple submitters, no conflicts
1165411	NM_017763.6(RNF43):c.576G>A (p.Pro192=)	RNF43	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1166912	NM_017763.6(RNF43):c.597G>A (p.Val199=)	RNF43	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1167774	NM_017763.6(RNF43):c.1093G>A (p.Ala365Thr)	RNF43	Benign	criteria provided, multiple submitters, no conflicts
1167880	NM_017763.6(RNF43):c.1585C>T (p.Arg529Trp)	RNF43	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1168015	NM_017763.6(RNF43):c.1821G>A (p.Ser607=)	RNF43	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

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).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04906343	Not specified	COMPLETED	Endoscopic Surveillance in Serrated Polyposis Syndrome and Low-risk of Advanced Neoplasia