Is APC p.Ser2005fs (c.6011_6012insTT) pathogenic?

APC p.Ser2005fs (c.60116012insTT) is classified Pathogenic in APC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-09). Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Ser2005fs (c.6011_6012insTT)?

APC p.Ser2005fs (c.6011_6012insTT) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ser2005fs (c.6011_6012insTT) in the general population?

APC p.Ser2005fs (c.6011_6012insTT) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

APC p.Ser2005fs

c.6011_6012insTT · rs1561604514 · VCV575384

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

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 4.1	GERP 2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,374 alleles

Overall 6.2e-05% 1/1,613,414 alleles · very rare exomes 1/1,461,122 · genomes 0/152,292 · 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.Ser2005fs
Coding: c.6011_6012insTT
MANE Select: NM_000038
dbSNP: rs1561604514
Type: Insertion
Location: chr5:112841605 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2005: 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.Ser2005Ter Pathogenic/Likely pathogenic ★★ same residue
APC p.Ser2005Leu Uncertain significance ★★ same residue
APC p.Ser2005= Likely benign ★ same residue
APC p.Glu1265delinsAlaTer Pathogenic/Likely pathogenic ★★ same condition
APC p.Glu129fs Pathogenic ★★ same condition
APC p.Ile55fs Pathogenic ★★ same condition
APC p.Leu1129fs Pathogenic ★★ same condition
APC p.Leu922fs 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-ser2005fs (accessed [today's date]).

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