Is POLE p.Pro1226fs (c.3677_3678del) pathogenic?

POLE p.Pro1226fs (c.36773678del) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-09). Very rare (popmax 0.01%, amr); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Pro1226fs (c.3677_3678del)?

POLE p.Pro1226fs (c.3677_3678del) is associated with colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Pro1226fs (c.3677_3678del) in the general population?

POLE p.Pro1226fs (c.3677_3678del) is very rare (popmax 0.01%, amr) (gnomAD).

POLE p.Pro1226fs

c.3677_3678del · rs765645032 · VCV540691

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Conditions

colorectal cancer, susceptibility to, 12

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 30 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.9	GERP -3.7
Overall
CADD	25.5	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 0.01% Admixed American · 6/60,030 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00062% 10/1,614,196 alleles · very rare exomes 8/1,461,872 · genomes 2/152,324 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,005
European (non-Finnish)	0.000339%	295,010

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: POLE
Protein: p.Pro1226fs
Coding: c.3677_3678del
MANE Select: NM_006231
dbSNP: rs765645032
Type: Deletion
Location: chr12:132649794 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1226: a UniProt-annotated variant site (in imagei)

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

Disease context

colorectal cancer, susceptibility to, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

Similar variants

POLE p.Pro1226Ser Uncertain significance ★★ ⚠ same residue
POLE p.Pro1226= Likely benign ★★ same residue
POLE p.Pro1226Ala Uncertain significance ★ ⚠ same residue
POLE p.Pro1226Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Phe48fs Pathogenic/Likely pathogenic ★★ same condition
POLE c.1359+4_1359+74del Uncertain significance ★★ same condition
POLE c.206_211delCCGAGA Uncertain significance ★★ same condition
POLE c.3459+4del Uncertain significance ★★ 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/pole-p-pro1226fs (accessed [today's date]).

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