Is APC p.Arg1040= (c.3120G>A) pathogenic?

APC p.Arg1040= (c.3120G>A) is classified Benign/Likely benign in APC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-28). Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Arg1040= (c.3120G>A)?

APC p.Arg1040= (c.3120G>A) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Arg1040= (c.3120G>A) in the general population?

APC p.Arg1040= (c.3120G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

APC p.Arg1040=

c.3120G>A · rs2149884761 · VCV1131997

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1, phastCons 1
Overall
CADD	8.866	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,028 alleles

Overall 6.2e-05% 1/1,614,084 alleles · very rare exomes 1/1,461,828 · genomes 0/152,256 · 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: APC
Protein: p.Arg1040=
Coding: c.3120G>A
MANE Select: NM_000038
dbSNP: rs2149884761
Type: single nucleotide variant
Location: chr5:112838714 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1040: the 'responsible for down-regulation through a process mediated by direct ubiquitination' region; the 'interaction with catenins' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial adenomatous polyposis 1

Similar variants

APC p.Arg1040Trp Uncertain significance ★★ same residue
APC p.Arg1040Lys Uncertain significance ★ same residue
APC p.Arg1040Thr Uncertain significance ★ 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
APC c.1409-3T>G 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-arg1040 (accessed [today's date]).

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