Is APC p.Arg1069Gly (c.3205A>G) pathogenic?

APC p.Arg1069Gly (c.3205A>G) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1875); Very rare (popmax 0.0022%, sas); Associated with Hereditary cancer.

What condition is associated with APC p.Arg1069Gly (c.3205A>G)?

APC p.Arg1069Gly (c.3205A>G) is associated with Hereditary cancer, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Arg1069Gly (c.3205A>G) in the general population?

APC p.Arg1069Gly (c.3205A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about APC p.Arg1069Gly (c.3205A>G)?

AlphaMissense predicts likely benign (score 0.1875) — an in-silico prediction, not a clinical call.

APC p.Arg1069Gly

c.3205A>G · rs375408871 · VCV142240

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Hereditary cancer

Computational evidence

Protein change
AlphaMissense	0.1875	likely benign
REVEL	0.523	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -1.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,681 bp · p 0.023 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00142% 23/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,497
South Asiangrpmax	0.0022%	45,540
Admixed American	0.00167%	60,012
African / African-American	0.00133%	74,958
European (non-Finnish)	0.00119%	84,289

Remaining individuals 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.Arg1069Gly
Coding: c.3205A>G
MANE Select: NM_000038
dbSNP: rs375408871
Type: single nucleotide variant
Location: chr5:112838799 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1069: 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 cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial adenomatous polyposis 1 classic or attenuated familial adenomatous polyposis

Similar variants

APC p.Arg1069Lys Uncertain significance ★★ same residue
APC p.Arg1069Met Uncertain significance ★★ same residue
APC p.Arg1069Ser Uncertain significance ★★ same residue
APC p.Arg1069= Likely benign ★★ same residue
APC p.Arg1069Thr Uncertain significance ★ same residue
APC p.Arg1069fs Pathogenic ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G 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-arg1069gly (accessed [today's date]).

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