Is RNF43 p.Pro310Ser (c.928C>T) pathogenic?

RNF43 p.Pro310Ser (c.928C>T) is classified Uncertain significance in RNF43 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-27). AlphaMissense: likely pathogenic (0.9836); Very rare (popmax 8.48e-05%, nfe).

How common is RNF43 p.Pro310Ser (c.928C>T) in the general population?

RNF43 p.Pro310Ser (c.928C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RNF43 p.Pro310Ser (c.928C>T)?

AlphaMissense predicts likely pathogenic (score 0.9836) — an in-silico prediction, not a clinical call.

RNF43 p.Pro310Ser

c.928C>T · rs1972801645 · VCV1443355

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9836	likely pathogenic · top 5% in RNF43
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -14.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 61 kb · p 1.7e-13 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,862 alleles

Overall 6.2e-05% 1/1,613,880 alleles · very rare exomes 1/1,461,666 · genomes 0/152,214 · joint denominator

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.Pro310Ser
Coding: c.928C>T
MANE Select: NM_017763
dbSNP: rs1972801645
Type: single nucleotide variant
Location: chr17:58360173 (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

Similar variants

RNF43 p.Pro310Leu Uncertain significance ★ ⚠ same residue
RNF43 p.Pro310= Likely benign ★ 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-pro310ser (accessed [today's date]).

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