Is RNF43 p.Pro660fs (c.1976dup) pathogenic?

RNF43 p.Pro660fs (c.1976dup) is classified Conflicting classifications of pathogenicity in RNF43 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-12-29). Very rare (popmax 0.00673%, afr); Associated with sessile serrated polyposis cancer syndrome.

What condition is associated with RNF43 p.Pro660fs (c.1976dup)?

RNF43 p.Pro660fs (c.1976dup) is associated with sessile serrated polyposis cancer syndrome (ClinVar).

How common is RNF43 p.Pro660fs (c.1976dup) in the general population?

RNF43 p.Pro660fs (c.1976dup) is very rare (popmax 0.00673%, afr) (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.Pro660fs

c.1976dup · rs755128667 · VCV1319730

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00673%, afr)

Conditions

sessile serrated polyposis cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.12	GERP -3.7
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00673% African / African-American · 5/74,302 alleles

Filtering AF 0.00257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00163%

Overall 0.00242% 39/1,612,386 alleles · very rare exomes 34/1,461,746 · genomes 5/150,640 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00673%	14,860
Remaining individualsnot grpmax-eligible	0.0064%	15,615
Admixed American	0.00334%	29,917
South Asian	0.0022%	45,496
European (non-Finnish)	0.00212%	47,185
Finnishnot grpmax-eligible	0.00157%	63,818

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.Pro660fs
Coding: c.1976dup
MANE Select: NM_017763
dbSNP: rs755128667
Type: Duplication
Location: chr17:58357799 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 55.86 · 2 PDB
Residue 660: 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 c.253-9dup Likely benign ★★ same condition
RNF43 c.376-13dup Likely benign ★★ same condition
RNF43 p.Pro660= Likely benign ★★ same residue
RNF43 p.Arg117fs Pathogenic ★ same condition
RNF43 p.Arg404fs Pathogenic ★ same condition
RNF43 p.Arg657fs Likely pathogenic ★ same condition
RNF43 p.Gly540fs Pathogenic ★ same condition
RNF43 p.Ser419fs Pathogenic ★ 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-pro660fs (accessed [today's date]).

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