Is APC p.Pro2540fs (c.7619del) pathogenic?

APC p.Pro2540fs (c.7619del) is classified Pathogenic/Likely pathogenic in APC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-02). Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Pro2540fs (c.7619del)?

APC p.Pro2540fs (c.7619del) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Pro2540fs (c.7619del) in the general population?

APC p.Pro2540fs (c.7619del) is very rare (popmax 0.00134%, afr) (gnomAD).

APC p.Pro2540fs

c.7619del · rs1172624671 · VCV2583238

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

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 -1.8	GERP -5.7
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,898 alleles

Overall 6.2e-05% 1/1,613,666 alleles · very rare exomes 0/1,461,534 · genomes 1/152,132 · 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.Pro2540fs
Coding: c.7619del
MANE Select: NM_000038
dbSNP: rs1172624671
Type: Deletion
Location: chr5:112843212 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2540: the 'disordered' region; the 'basic region' region; the 'interaction with dlg1' 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.Pro2540_Ile2541insTer Pathogenic ★ same residue
APC p.Pro2540Ala Uncertain significance ★★ same residue
APC p.Pro2540Gln Uncertain significance ★★ same residue
APC p.Pro2540Leu Uncertain significance ★★ same residue
APC p.Pro2540= 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-pro2540fs (accessed [today's date]).

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