Is POLE p.Cys727Arg (c.2179T>C) pathogenic?

POLE p.Cys727Arg (c.2179T>C) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.995); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Cys727Arg (c.2179T>C)?

POLE p.Cys727Arg (c.2179T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Cys727Arg (c.2179T>C) in the general population?

POLE p.Cys727Arg (c.2179T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about POLE p.Cys727Arg (c.2179T>C)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

POLE p.Cys727Arg

c.2179T>C · rs1060500832 · VCV1787228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic · top 6% in POLE
REVEL	0.692	pathogenic-leaning
SaProt	LLR -14.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	26.2	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 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.2e-05% 1/1,614,160 alleles · very rare exomes 1/1,461,806 · genomes 0/152,354 · 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: POLE
Protein: p.Cys727Arg
Coding: c.2179T>C
MANE Select: NM_006231
dbSNP: rs1060500832
Type: single nucleotide variant
Location: chr12:132667643 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 727: an α-helix; 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 p.Cys727Ser Uncertain significance ★★ ⚠ same residue
POLE p.Cys727Tyr Uncertain significance ★ ⚠ same residue
POLE p.Cys727= 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-cys727arg (accessed [today's date]).

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