Is RNF43 p.Pro756Arg (c.2267C>G) pathogenic?

RNF43 p.Pro756Arg (c.2267C>G) is classified Uncertain significance in RNF43 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0815); Very rare (popmax 0.00533%, afr); Associated with sessile serrated polyposis cancer syndrome.

What condition is associated with RNF43 p.Pro756Arg (c.2267C>G)?

RNF43 p.Pro756Arg (c.2267C>G) is associated with sessile serrated polyposis cancer syndrome (ClinVar).

How common is RNF43 p.Pro756Arg (c.2267C>G) in the general population?

RNF43 p.Pro756Arg (c.2267C>G) is very rare (popmax 0.00533%, afr) (gnomAD).

How is Serrated polyposis syndrome inherited?

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

What do computational predictors say about RNF43 p.Pro756Arg (c.2267C>G)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

RNF43 p.Pro756Arg

c.2267C>G · rs757324156 · VCV1011805

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sessile serrated polyposis cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 2, phastCons 0.99
Regional constraint	o/e 0.77	unconstrained · MANE · 61 kb · p 1.7e-13 · regional, not allelic
Overall
CADD	15.52	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,062 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000434% 7/1,614,236 alleles · very rare exomes 7/1,461,888 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,765
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	8.47e-05%	1,180,043

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.Pro756Arg
Coding: c.2267C>G
MANE Select: NM_017763
dbSNP: rs757324156
Type: single nucleotide variant
Location: chr17:58357509 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 55.86 · 2 PDB
Residue 756: the 'disordered' region

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.Pro756= Benign/Likely benign ★★ same residue
RNF43 p.Pro756Ser 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-pro756arg (accessed [today's date]).

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