Is RNF43 p.Arg657Pro (c.1970G>C) pathogenic?

RNF43 p.Arg657Pro (c.1970G>C) is classified Benign in RNF43 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.149); Low-frequency (popmax 2.03%, sas); Associated with hyperplastic polyposis syndrome.

What condition is associated with RNF43 p.Arg657Pro (c.1970G>C)?

RNF43 p.Arg657Pro (c.1970G>C) is associated with hyperplastic polyposis syndrome (ClinVar).

How common is RNF43 p.Arg657Pro (c.1970G>C) in the general population?

RNF43 p.Arg657Pro (c.1970G>C) is low-frequency (popmax 2.03%, sas) (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.Arg657Pro (c.1970G>C)?

AlphaMissense predicts likely benign (score 0.149) — an in-silico prediction, not a clinical call.

RNF43 p.Arg657Pro

c.1970G>C · rs142097313 · VCV1170563

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.149 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.03%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperplastic polyposis syndrome

Computational evidence

Protein change
AlphaMissense	0.149	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.75	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 3.3	GERP 0.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 61 kb · p 1.7e-13 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.03% South Asian · 1,851/91,082 alleles

Filtering AF 1.96% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.92%

Overall 0.127% 2,044/1,614,144 alleles · low-frequency exomes 1,924/1,461,852 · genomes 120/152,292 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.03%	49
Remaining individualsnot grpmax-eligible	0.147%	679
Ashkenazi Jewishnot grpmax-eligible	0.108%	925
Middle Eastern	0.099%	1,010
African / African-American	0.0107%	9,380
European (non-Finnish)	0.00449%	22,265
East Asian	0.00223%	44,874
Admixed American	0.00167%	60,024

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.Arg657Pro
Coding: c.1970G>C
MANE Select: NM_017763
dbSNP: rs142097313
Type: single nucleotide variant
Location: chr17:58357806 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 55.86 · 2 PDB
Residue 657: the 'disordered' region

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

Disease context

hyperplastic polyposis 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.Arg657Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
RNF43 p.Arg657Gln Uncertain significance ★★ ⚠ same residue
RNF43 p.Arg529Gln Uncertain significance ★★ ⚠ same condition
RNF43 p.Arg654Lys Uncertain significance ★★ ⚠ same condition
RNF43 p.Asp261Glu Uncertain significance ★★ ⚠ same condition
RNF43 p.Leu214Val Uncertain significance ★★ ⚠ same condition
RNF43 p.Pro569Ser Uncertain significance ★★ ⚠ same condition
RNF43 p.Pro87Leu 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-arg657pro (accessed [today's date]).

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