Is APC2 p.Thr259fs (c.774del) pathogenic?

APC2 p.Thr259fs (c.774del) is classified Likely pathogenic in APC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). Very rare (popmax 8.49e-05%, nfe); Associated with APC2-related disorder.

What condition is associated with APC2 p.Thr259fs (c.774del)?

APC2 p.Thr259fs (c.774del) is associated with APC2-related disorder (ClinVar).

How common is APC2 p.Thr259fs (c.774del) in the general population?

APC2 p.Thr259fs (c.774del) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

APC2 p.Thr259fs

c.774del · VCV4939675

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

APC2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.21	GERP 0.2, phastCons 0.04

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,230 alleles

Overall 6.86e-05% 1/1,457,106 alleles · very rare

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: APC2
Protein: p.Thr259fs
Coding: c.774del
MANE Select: NM_005883
Type: Deletion
Location: chr19:1456359 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 259: the 'disordered' region; a UniProt-annotated variant site (in cdcbm10)

Full APC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

APC2-related disorder

Similar variants

APC2 p.Cys974fs Likely pathogenic same condition
APC2 p.1307GAG[1] Uncertain significance ★★ same condition
APC2 p.Arg853Pro Uncertain significance ★★ ⚠ same condition
APC2 p.Gln1000Lys Uncertain significance ★★ ⚠ same condition
APC2 p.Pro1253Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Pro2066Ala Uncertain significance ★★ ⚠ same condition
APC2 p.Glu220fs Pathogenic ★ same condition
APC2 p.His734fs 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/apc2-p-thr259fs (accessed [today's date]).

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