Is POLE p.Glu396= (c.1188G>A) pathogenic?

POLE p.Glu396= (c.1188G>A) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.048%, afr); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Glu396= (c.1188G>A)?

POLE p.Glu396= (c.1188G>A) is associated with colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Glu396= (c.1188G>A) in the general population?

POLE p.Glu396= (c.1188G>A) is ultra-rare (popmax 0.048%, afr) (gnomAD).

POLE p.Glu396=

c.1188G>A · rs371717068 · VCV413556

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.1	GERP -0.39, phastCons 0.94
Overall
CADD	8.534	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.048% African / African-American · 36/74,936 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00223% 36/1,614,070 alleles · ultra-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: POLE
Protein: p.Glu396=
Coding: c.1188G>A
MANE Select: NM_006231
dbSNP: rs371717068
Type: single nucleotide variant
Location: chr12:132675436 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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.Glu396Gln Uncertain significance ★ ⚠ same residue
POLE p.Glu396Lys Uncertain significance ★ ⚠ same residue
POLE p.Glu396Ter Conflicting classifications of pathogenicity ★ same residue
POLE p.Glu396Gly Uncertain significance ★★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A 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-glu396 (accessed [today's date]).

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