Is RNF43 p.Ser378Pro (c.1132T>C) pathogenic?

RNF43 p.Ser378Pro (c.1132T>C) is classified Uncertain significance in RNF43 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-12). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.00136%, afr).

How common is RNF43 p.Ser378Pro (c.1132T>C) in the general population?

RNF43 p.Ser378Pro (c.1132T>C) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about RNF43 p.Ser378Pro (c.1132T>C)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

RNF43 p.Ser378Pro

c.1132T>C · rs1972760041 · VCV1041451

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -5.95	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 1.3	GERP 0.55, phastCons 0.06
Regional constraint	o/e 0.77	unconstrained · MANE · 61 kb · p 1.7e-13 · regional, not allelic
Overall
CADD	17.98	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00136% African / African-American · 1/73,342 alleles

Overall 6.52e-05% 1/1,533,332 alleles · very rare exomes 1/1,381,064 · genomes 0/152,268 · 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.Ser378Pro
Coding: c.1132T>C
MANE Select: NM_017763
dbSNP: rs1972760041
Type: single nucleotide variant
Location: chr17:58358644 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 55.86 · 2 PDB
Residue 378: the 'disordered' region

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

Similar variants

RNF43 p.Ser378Cys Uncertain significance ★★ ⚠ same residue
RNF43 p.Ser378fs Pathogenic ★ 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-ser378pro (accessed [today's date]).

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