Is POLE p.Glu682Lys (c.2044G>A) pathogenic?

POLE p.Glu682Lys (c.2044G>A) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-11). AlphaMissense: likely pathogenic (0.9535); Very rare (popmax 0.00112%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Glu682Lys (c.2044G>A)?

POLE p.Glu682Lys (c.2044G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Glu682Lys (c.2044G>A) in the general population?

POLE p.Glu682Lys (c.2044G>A) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about POLE p.Glu682Lys (c.2044G>A)?

AlphaMissense predicts likely pathogenic (score 0.9535) — an in-silico prediction, not a clinical call.

POLE p.Glu682Lys

c.2044G>A · rs878854848 · VCV240416

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9535 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9535	likely pathogenic
REVEL	0.448	indeterminate
SaProt	LLR -10.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00112% South Asian · 1/89,100 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000187% 3/1,600,942 alleles · very rare exomes 3/1,448,634 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00112%	89,100
European (non-Finnish)	0.000171%	586,390

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.Glu682Lys
Coding: c.2044G>A
MANE Select: NM_006231
dbSNP: rs878854848
Type: single nucleotide variant
Location: chr12:132668485 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 682: an α-helix

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 p.Glu682Val Uncertain significance ★★ ⚠ same residue
POLE p.Glu682Ala Uncertain significance ★ ⚠ same residue
POLE p.Glu682= Likely benign ★ same residue
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

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-glu682lys (accessed [today's date]).

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