Is APC p.Glu1663Lys (c.4987G>A) pathogenic?

APC p.Glu1663Lys (c.4987G>A) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-03-20). AlphaMissense: likely pathogenic (0.8507); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Glu1663Lys (c.4987G>A)?

APC p.Glu1663Lys (c.4987G>A) is associated with hereditary neoplastic syndrome, gastric cancer, colorectal cancer (ClinVar).

How common is APC p.Glu1663Lys (c.4987G>A) in the general population?

APC p.Glu1663Lys (c.4987G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about APC p.Glu1663Lys (c.4987G>A)?

AlphaMissense predicts likely pathogenic (score 0.8507) — an in-silico prediction, not a clinical call.

APC p.Glu1663Lys

c.4987G>A · rs758987855 · VCV216168

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8507	likely pathogenic
REVEL	0.355	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 4,236 bp · p 0.00065 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.2e-05% 1/1,614,100 alleles · very rare exomes 1/1,461,838 · genomes 0/152,262 · 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.Glu1663Lys
Coding: c.4987G>A
MANE Select: NM_000038
dbSNP: rs758987855
Type: single nucleotide variant
Location: chr5:112840581 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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: gastric cancer colorectal cancer hepatocellular carcinoma gastric adenocarcinoma and proximal polyposis of the stomach familial adenomatous polyposis 1

Similar variants

APC p.Glu1663Ter Pathogenic ★★ same residue
APC p.Glu1663= Benign/Likely benign ★★ same residue
APC p.Glu1663Asp 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-glu1663lys (accessed [today's date]).

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