Is RNF43 p.Pro686Arg (c.2057C>G) pathogenic?

RNF43 p.Pro686Arg (c.2057C>G) is classified Benign in RNF43 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0837); Common (popmax 15.3%, mid) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with RNF43 p.Pro686Arg (c.2057C>G)?

RNF43 p.Pro686Arg (c.2057C>G) is associated with hereditary neoplastic syndrome, sessile serrated polyposis cancer syndrome (ClinVar).

What do computational predictors say about RNF43 p.Pro686Arg (c.2057C>G)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

RNF43 p.Pro686Arg

Q: How common is RNF43 p.Pro686Arg (c.2057C>G) in the general population?

RNF43 p.Pro686Arg (c.2057C>G) is common (popmax 15.3%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2057C>G · rs9652855 · VCV1169209

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 15.3%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -7.81	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 5.7	GERP -0.26, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 61 kb · p 1.7e-13 · regional, not allelic
Overall
CADD	7.655	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 15.3% Middle Eastern · 922/6,044 alleles

Filtering AF 14.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.1%

Overall 11.4% 183,759/1,611,466 alleles · common exomes 166,749/1,459,162 · genomes 17,010/152,304 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	17.2%	6
Middle Easterngrpmax	15.3%	7
European (non-Finnish)	12.4%	8
African / African-American	12%	8
Remaining individualsnot grpmax-eligible	11.6%	9
Finnishnot grpmax-eligible	9.7%	10
Admixed American	7.16%	14
Amishnot grpmax-eligible	6.36%	16
South Asian	5.94%	17
East Asian	0.0201%	4,986

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro686Arg
Coding: c.2057C>G
MANE Select: NM_017763
dbSNP: rs9652855
Type: single nucleotide variant
Location: chr17:58357719 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 55.86 · 2 PDB
Residue 686: a UniProt-annotated variant site (in)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sessile serrated polyposis cancer syndrome

Similar variants

RNF43 p.Pro686Thr Uncertain significance ★★ ⚠ same residue
RNF43 p.Pro686Ser Uncertain significance ★ ⚠ same residue
RNF43 p.Pro686= Likely benign ★ same residue
RNF43 p.Pro686His Likely benign ★ 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

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-pro686arg (accessed [today's date]).

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