Is RNF43 p.Pro229= (c.687G>A) pathogenic?

RNF43 p.Pro229= (c.687G>A) is classified Uncertain significance in RNF43 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-19). Very rare (popmax 0.00663%, nfe); Associated with sessile serrated polyposis cancer syndrome.

What condition is associated with RNF43 p.Pro229= (c.687G>A)?

RNF43 p.Pro229= (c.687G>A) is associated with sessile serrated polyposis cancer syndrome (ClinVar).

How common is RNF43 p.Pro229= (c.687G>A) in the general population?

RNF43 p.Pro229= (c.687G>A) is very rare (popmax 0.00663%, nfe) (gnomAD).

How is Serrated polyposis syndrome inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

RNF43 p.Pro229=

c.687G>A · rs779321417 · VCV859421

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00663%, nfe)

Conditions

sessile serrated polyposis cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.50	donor gain · deltas
Pangolin	Δ0.51	loss · gain 0.33 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 4.2	GERP -0.22, phastCons 1
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00663% European (non-Finnish) · 78/1,176,714 alleles

Filtering AF 0.0054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00499%

Overall 0.00491% 79/1,607,532 alleles · very rare exomes 73/1,455,310 · genomes 6/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00663%	15,086
African / African-American	0.00134%	74,666

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RNF43
Protein: p.Pro229=
Coding: c.687G>A
MANE Select: NM_017763
dbSNP: rs779321417
Type: single nucleotide variant
Location: chr17:58362544 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 55.86 · 2 PDB

Full RNF43 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sessile serrated polyposis cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Serrated polyposis syndrome (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial, Unknown
Onset: Adult, Elderly
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

RNF43 p.Pro229Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
RNF43 p.Pro229Thr Uncertain significance ★ ⚠ same residue
RNF43 p.Arg337Ter Pathogenic/Likely pathogenic ★★ same condition
RNF43 c.688-3C>T Uncertain significance ★★ same condition
RNF43 p.Ala115Val Uncertain significance ★★ ⚠ same condition
RNF43 p.Ala126Val Uncertain significance ★★ ⚠ same condition
RNF43 p.Ala148Gly Uncertain significance ★★ ⚠ same condition
RNF43 p.Ala169Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rnf43-p-pro229 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown