Is APC p.Pro1458fs (c.4373_4380del) pathogenic?

APC p.Pro1458fs (c.43734380del) is classified Pathogenic/Likely pathogenic in APC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-05-10). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Pro1458fs (c.4373_4380del)?

APC p.Pro1458fs (c.4373_4380del) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Pro1458fs (c.4373_4380del) in the general population?

APC p.Pro1458fs (c.4373_4380del) is no gnomAD frequency available for this variant (gnomAD).

APC p.Pro1458fs

c.4373_4380del · rs2533570013 · VCV1740102

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 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 -0.52	GERP 0.34

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.Pro1458fs
Coding: c.4373_4380del
MANE Select: NM_000038
dbSNP: rs2533570013
Type: Deletion
Location: chr5:112839967 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1458: the 'disordered' region

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.Pro1458Leu Uncertain significance ★★ ⚠ same residue
APC p.Pro1458Ala Uncertain significance ★ ⚠ same residue
APC p.Pro1458Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
APC p.Pro1458Thr Uncertain significance ★ ⚠ same residue
APC p.Pro1458= Likely benign ★ same residue
APC c.1311_1312+1del Pathogenic ★★★ same condition
APC c.1312+4_1312+19del Likely pathogenic ★★★ same condition
APC p.Glu2172fs 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-pro1458fs (accessed [today's date]).

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