Is RNF43 p.Pro756= (c.2268A>G) pathogenic?

RNF43 p.Pro756= (c.2268A>G) is classified Benign/Likely benign in RNF43 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-21). Ultra-rare (popmax 0.069%, eas).

How common is RNF43 p.Pro756= (c.2268A>G) in the general population?

RNF43 p.Pro756= (c.2268A>G) is ultra-rare (popmax 0.069%, eas) (gnomAD).

RNF43 p.Pro756=

c.2268A>G · rs754064531 · VCV1166638

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.069%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.2	GERP -4
Overall
CADD	1.134	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.069% East Asian · 31/44,896 alleles

Filtering AF 0.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0434%

Overall 0.00211% 34/1,614,122 alleles · ultra-rare exomes 33/1,461,882 · genomes 1/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.069%	1,448
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000169%	590,023

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.Pro756=
Coding: c.2268A>G
MANE Select: NM_017763
dbSNP: rs754064531
Type: single nucleotide variant
Location: chr17:58357508 (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

Similar variants

RNF43 p.Pro756Arg Uncertain significance ★★ ⚠ same residue
RNF43 p.Pro756Ser Uncertain significance ★ ⚠ same residue
RNF43 p.Arg337Ter Pathogenic/Likely pathogenic ★★ same type
RNF43 c.252+2C>G Uncertain significance ★★ same type
RNF43 c.687+5G>T Uncertain significance ★★ same type
RNF43 c.688-3C>T Uncertain significance ★★ same type
RNF43 p.Ala115Asp Uncertain significance ★★ ⚠ same type
RNF43 p.Ala115Val Uncertain significance ★★ ⚠ same type

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-pro756 (accessed [today's date]).

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