Is POLE p.Glu2177= (c.6531G>A) pathogenic?

POLE p.Glu2177= (c.6531G>A) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Glu2177= (c.6531G>A)?

POLE p.Glu2177= (c.6531G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Glu2177= (c.6531G>A) in the general population?

POLE p.Glu2177= (c.6531G>A) is absent from gnomAD v4.1 (gnomAD).

POLE p.Glu2177=

c.6531G>A · VCV4141195

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.78	donor loss · deltas
Pangolin	Δ0.72	loss · gain 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Overall
CADD	20.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLE
Protein: p.Glu2177=
Coding: c.6531G>A
MANE Select: NM_006231
Type: single nucleotide variant
Location: chr12:132626117 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2177: a UniProt-annotated variant site (in imagei)

Full POLE 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

Similar variants

POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A Uncertain significance ★★ same condition
POLE c.1106+3G>C Uncertain significance ★★ same condition
POLE c.1106+4A>G Uncertain significance ★★ same condition
POLE c.1226+3A>G Uncertain significance ★★ same condition
POLE c.1359+4C>A Uncertain significance ★★ same condition
POLE c.1474-3C>G 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-glu2177 (accessed [today's date]).

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