Is RNF43 p.Pro372Ser (c.1114C>T) pathogenic?

RNF43 p.Pro372Ser (c.1114C>T) is classified Conflicting classifications of pathogenicity in RNF43 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.0796); Ultra-rare (popmax 0.0493%, nfe); Associated with hyperplastic polyposis syndrome.

What condition is associated with RNF43 p.Pro372Ser (c.1114C>T)?

RNF43 p.Pro372Ser (c.1114C>T) is associated with hyperplastic polyposis syndrome, sessile serrated polyposis cancer syndrome (ClinVar).

How common is RNF43 p.Pro372Ser (c.1114C>T) in the general population?

RNF43 p.Pro372Ser (c.1114C>T) is ultra-rare (popmax 0.0493%, nfe) (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.Pro372Ser (c.1114C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

RNF43 p.Pro372Ser

c.1114C>T · rs201204271 · VCV953598

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperplastic polyposis syndrome

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -7.04	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 2.9	GERP 0.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 61 kb · p 1.7e-13 · regional, not allelic
Overall
CADD	14.25	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 0.0493% European (non-Finnish) · 560/1,135,900 alleles

Filtering AF 0.0459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.0399% 610/1,527,690 alleles · ultra-rare exomes 578/1,375,478 · genomes 32/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0493%	2,028
Finnishnot grpmax-eligible	0.0411%	2,435
Remaining individualsnot grpmax-eligible	0.0305%	3,278
Middle Eastern	0.0172%	5,828
Admixed American	0.00625%	15,989
African / African-American	0.00548%	18,236

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.Pro372Ser
Coding: c.1114C>T
MANE Select: NM_017763
dbSNP: rs201204271
Type: single nucleotide variant
Location: chr17:58358662 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 55.86 · 2 PDB
Residue 372: 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

Also linked: sessile serrated polyposis cancer syndrome

For Serrated polyposis syndrome (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial, Unknown
Onset: Adult, Elderly
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

RNF43 p.Pro372= 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
RNF43 p.Ala148Gly Uncertain significance ★★ ⚠ same condition
RNF43 p.Ala169Ser Uncertain significance ★★ ⚠ same condition
RNF43 p.Ala193Val 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-pro372ser (accessed [today's date]).

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