Is APC p.Glu565= (c.1695A>G) pathogenic?

APC p.Glu565= (c.1695A>G) is classified Benign in APC (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). Low-frequency (popmax 3.56%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Glu565= (c.1695A>G)?

APC p.Glu565= (c.1695A>G) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Glu565= (c.1695A>G) in the general population?

APC p.Glu565= (c.1695A>G) is low-frequency (popmax 3.56%, afr) (gnomAD).

APC p.Glu565=

c.1695A>G · rs77921116 · VCV183766

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.56%, 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 8.1	GERP 2.6, phastCons 1
Overall
CADD	12.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.56% African / African-American · 2,668/75,014 alleles

Filtering AF 3.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.4%

Overall 0.195% 3,142/1,613,928 alleles · low-frequency exomes 1,490/1,461,626 · genomes 1,652/152,302 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.56%	28
Admixed American	0.367%	273
Remaining individualsnot grpmax-eligible	0.28%	357
Middle Eastern	0.116%	865
South Asian	0.011%	9,108
European (non-Finnish)	0.00517%	19,343
East Asian	0.00223%	44,854

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.Glu565=
Coding: c.1695A>G
MANE Select: NM_000038
dbSNP: rs77921116
Type: single nucleotide variant
Location: chr5:112828924 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 565: an α-helix

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.Glu565Ter Pathogenic ★★ same residue
APC p.Glu565Asp Uncertain significance ★★ same residue
APC p.Glu565Lys Uncertain significance ★★ same residue
APC p.Glu565Gly 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

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-glu565 (accessed [today's date]).

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