Is APC p.Glu582= (c.1746A>G) pathogenic?

APC p.Glu582= (c.1746A>G) is classified Benign in APC (ClinVar, Expert panel, 9 submitters; last evaluated 2023-02-19). Very rare (popmax 0.004%, afr); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Glu582= (c.1746A>G)?

APC p.Glu582= (c.1746A>G) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome, classic or attenuated familial adenomatous polyposis (ClinVar).

How common is APC p.Glu582= (c.1746A>G) in the general population?

APC p.Glu582= (c.1746A>G) is very rare (popmax 0.004%, afr) (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.Glu582=

c.1746A>G · rs876658969 · VCV231116

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

familial adenomatous polyposis 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

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

BS2 BS1 BP7 BP4

Curation rationale (ClinGen, verbatim)

The c.1746A>G (p.Glu582=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). This variant has been observed in a heterozygous state in 12 unrelated healthy adult individuals worth 12 (≥ 10) healthy individual points in total (BS2; Ambry internal data). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 0.0001148 in African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis threshold (≥ 0.0001) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BS1, BS2, BP4, and BP7 (VCEP specifications version 1; date of approval: 12/12/2022).

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -3.2, phastCons 1
Overall
CADD	9.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,912 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,613,712 alleles · very rare exomes 3/1,461,516 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,971
European (non-Finnish)	0.00017%	589,883

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.Glu582=
Coding: c.1746A>G
MANE Select: NM_000038
dbSNP: rs876658969
Type: single nucleotide variant
Location: chr5:112834953 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 582: 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: hereditary neoplastic syndrome classic or attenuated familial adenomatous polyposis

For Familial adenomatous polyposis (Orphanet):

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

Similar variants

APC p.Glu582Ter Pathogenic ★ same residue
APC p.Glu582Asp Uncertain significance ★ same residue
APC p.Glu582Gln Uncertain significance ★ same residue
APC p.Glu582Gly 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-glu582 (accessed [today's date]).

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