APC p.Arg232Ter
c.694C>T · rs397515734 · VCV42248
ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
Pathogenic for familial adenomatous polyposis 1. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PS4
Curation rationale (ClinGen, verbatim)
The NM_000038.6:c.694C>T p.(Arg232Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 7 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in at least 10 probands meeting phenotypic criteria, resulting in a total phenotype score of > 4 (PS4, [PMID: 1316610, 20223039, 7524601, 21110124, 19279422 and several more]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4 and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | predicted | premature termination codon in exon 7 of 16 |
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 3.3 | phastCons 1 |
| Overall | ||
| CADD | 37.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
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
- APC
- Protein
- p.Arg232Ter
- Coding
- c.694C>T
- MANE Select
- NM_000038
- dbSNP
- rs397515734
- Type
- single nucleotide variant
- Location
- chr5:112792494 (GRCh38)
- Gene constraint
- LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Residue 232
- an α-helix
Disease context
familial adenomatous polyposis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: colon carcinomahepatocellular carcinomahereditary neoplastic syndromeclassic familial adenomatous polyposisgastric neoplasm
For Familial adenomatous polyposis (Orphanet):
- Inheritance
- Autosomal dominant, Autosomal recessive
- Onset
- Adult
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- APC p.Arg232Gln Conflicting classifications of pathogenicity ★ same residue
- APC p.Arg232Leu Uncertain significance ★ ⚠ same residue
- APC p.Arg232Pro Uncertain significance ★ same residue
- APC p.Arg232= Benign ★ same residue
- APC c.1312+3A>C Likely pathogenic ★★★ same condition
- APC c.1312+3A>G Pathogenic ★★★ same condition
- APC c.1312+5G>A Likely pathogenic ★★★ same condition
- APC c.1312+5G>C Likely pathogenic ★★★ 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/apc-p-arg232ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown