Is APC p.Glu658fs (c.1972_1975del) pathogenic?

APC p.Glu658fs (c.19721975del) is classified Pathogenic in APC (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-04-11). Absent from gnomAD; Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Glu658fs (c.1972_1975del)?

APC p.Glu658fs (c.1972_1975del) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Glu658fs (c.1972_1975del) in the general population?

APC p.Glu658fs (c.1972_1975del) is absent from gnomAD (gnomAD).

APC p.Glu658fs

c.1972_1975del · rs863225322 · VCV217940

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (16 of 16) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP 1.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: APC
Protein: p.Glu658fs
Coding: c.1972_1975del
MANE Select: NM_000038
dbSNP: rs863225322
Type: Microsatellite
Location: chr5:112837563 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 658: 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.Glu658Gln Uncertain significance ★★ same residue
APC p.Glu658Lys Uncertain significance ★★ same residue
APC p.Glu658Met Uncertain significance ★★ same residue
APC p.Glu658Val Uncertain significance ★★ same residue
APC p.Glu658= Benign/Likely benign ★★ same residue
APC p.Glu658_Asn659insLys Uncertain significance ★ same residue
APC p.Glu658Gly Uncertain significance ★ same residue
APC c.531+5_531+8del 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-glu658fs (accessed [today's date]).

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