Is APC p.Arg216Ter (c.646C>T) pathogenic?

APC p.Arg216Ter (c.646C>T) is classified Pathogenic in APC (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-01-19). Very rare (popmax 0.00134%, afr); Associated with APC associated polyposis.

What condition is associated with APC p.Arg216Ter (c.646C>T)?

APC p.Arg216Ter (c.646C>T) is associated with APC associated polyposis, gastric cancer, colon carcinoma (ClinVar).

How common is APC p.Arg216Ter (c.646C>T) in the general population?

APC p.Arg216Ter (c.646C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

APC p.Arg216Ter

c.646C>T · rs62619935 · VCV127312

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

APC associated polyposis

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,604 alleles

Overall 0.000659% 1/151,784 alleles · very rare

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.Arg216Ter
Coding: c.646C>T
MANE Select: NM_000038
dbSNP: rs62619935
Type: single nucleotide variant
Location: chr5:112792446 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 216: an α-helix

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

Disease context

APC associated polyposis

Also linked: gastric cancer colon carcinoma colorectal cancer hepatocellular carcinoma hereditary neoplastic syndrome gastric adenocarcinoma and proximal polyposis of the stomach classic familial adenomatous polyposis familial adenomatous polyposis 1 classic or attenuated familial adenomatous polyposis gastric neoplasm

Similar variants

APC p.Arg216= Conflicting classifications of pathogenicity ★ same residue
APC p.Arg216Gln Conflicting classifications of pathogenicity ★ same residue
APC p.Arg216Gly Conflicting classifications of pathogenicity ★ same residue
APC p.Arg216Leu Uncertain significance ★ ⚠ same residue
APC p.Arg216fs Pathogenic ★ 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

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-arg216ter (accessed [today's date]).

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