Is RNF43 p.His697= (c.2091C>T) pathogenic?

RNF43 p.His697= (c.2091C>T) is classified Conflicting classifications of pathogenicity in RNF43 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-15). Ultra-rare (popmax 0.0312%, nfe); Associated with hyperplastic polyposis syndrome.

What condition is associated with RNF43 p.His697= (c.2091C>T)?

RNF43 p.His697= (c.2091C>T) is associated with hyperplastic polyposis syndrome (ClinVar).

How common is RNF43 p.His697= (c.2091C>T) in the general population?

RNF43 p.His697= (c.2091C>T) is ultra-rare (popmax 0.0312%, nfe) (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.His697=

c.2091C>T · rs199916345 · VCV1166587

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, nfe)

Conditions

hyperplastic polyposis syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -1.3, phastCons 1
Overall
CADD	2.268	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% European (non-Finnish) · 368/1,179,082 alleles

Filtering AF 0.0285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0275%

Overall 0.0364% 587/1,612,432 alleles · ultra-rare exomes 519/1,460,234 · genomes 68/152,198 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.256%	390
Ashkenazi Jewishnot grpmax-eligible	0.0782%	1,279
Remaining individualsnot grpmax-eligible	0.0385%	2,599
European (non-Finnish)grpmax	0.0312%	3,204
Middle Eastern	0.0165%	6,078
African / African-American	0.00935%	10,700

Finnish 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.His697=
Coding: c.2091C>T
MANE Select: NM_017763
dbSNP: rs199916345
Type: single nucleotide variant
Location: chr17:58357685 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 55.86 · 2 PDB

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.His697Arg Uncertain significance ★★ ⚠ same residue
RNF43 p.His697Tyr 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-his697 (accessed [today's date]).

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