Is APC p.Arg24Ter (c.70C>T) pathogenic?

APC p.Arg24Ter (c.70C>T) is classified Uncertain significance in APC (ClinVar, Expert panel, 21 submitters; last evaluated 2025-05-15). Very rare (popmax 0.00223%, eas); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Arg24Ter (c.70C>T)?

APC p.Arg24Ter (c.70C>T) is associated with familial adenomatous polyposis 1, gastric cancer, colon carcinoma (ClinVar).

How common is APC p.Arg24Ter (c.70C>T) in the general population?

APC p.Arg24Ter (c.70C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Familial adenomatous polyposis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

APC p.Arg24Ter

c.70C>T · rs145945630 · VCV184702

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 21 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

familial adenomatous polyposis 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Uncertain Significance for familial adenomatous polyposis 1. Applied ACMG criteria (verbatim):

PS4_Supporting BS2

Curation rationale (ClinGen, verbatim)

The NM_000038.6(APC):c.70C>T (p.Arg24Ter) in APC is a nonsense variant located 5’ of codon 49, thus PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00002 (6/268,098 alleles), however, no value is given for the “filtering allele frequency” (FAF) (PM2_Supporting and BS1 not met). This variant has been observed in heterozygous state in 67 individuals, which are reported either with a very mild polyposis phenotype (only 3 carriers fulfilled 0.5 phenotype points each; PS4_Supporting) or without a colorectal cancer/polyposis associated phenotype (at least 10 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total; BS2) (PMID: 28135145 and 18433509, internal data Ambry Genetics, GeneDX and Labcorp Genetics (formerly Invitae)). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criterion PS4_Supporting and BS2 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 2 of 16
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Overall
CADD	40.0	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 0.00223% East Asian · 1/44,820 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00178% 26/1,461,502 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,144
East Asiangrpmax	0.00223%	44,820
Remaining individualsnot grpmax-eligible	0.0016%	62,494
European (non-Finnish)	0.00144%	69,399

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg24Ter
Coding: c.70C>T
MANE Select: NM_000038
dbSNP: rs145945630
Type: single nucleotide variant
Location: chr5:112754960 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 24: an α-helix

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

Disease context

familial adenomatous polyposis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer colon carcinoma hepatocellular carcinoma hereditary neoplastic syndrome attenuated familial adenomatous polyposis classic familial adenomatous polyposis classic or attenuated familial adenomatous polyposis gastric neoplasm

For Familial adenomatous polyposis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

APC p.Arg24Gln Uncertain significance ★★ same residue
APC p.Arg24Leu Uncertain significance ★★ same residue
APC p.Ser24Cys Uncertain significance ★★ same residue
APC p.Arg24Pro Uncertain significance ★ same residue
APC p.Ser24= Uncertain significance ★ same residue
APC p.Ser24Phe Conflicting classifications of pathogenicity ★ same residue
APC p.Arg24= Likely benign ★ same residue
APC c.1312+3A>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-arg24ter (accessed [today's date]).

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