Is POLE p.Ile2199= (c.6597C>T) pathogenic?

POLE p.Ile2199= (c.6597C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-29). Rare (popmax 0.564%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ile2199= (c.6597C>T)?

POLE p.Ile2199= (c.6597C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ile2199= (c.6597C>T) in the general population?

POLE p.Ile2199= (c.6597C>T) is rare (popmax 0.564%, eas) (gnomAD).

POLE p.Ile2199=

c.6597C>T · rs147611144 · VCV240604

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.564%, eas)

Conditions

hereditary neoplastic syndrome

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 -3.2
Overall
CADD	0.806	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.564% East Asian · 253/44,884 alleles

Filtering AF 0.507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.485%

Overall 0.0211% 341/1,613,690 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.564%	177
African / African-American	0.016%	6,256
Remaining individualsnot grpmax-eligible	0.0144%	6,946
European (non-Finnish)	0.00559%	17,879
South Asian	0.0011%	91,090

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.Ile2199=
Coding: c.6597C>T
MANE Select: NM_006231
dbSNP: rs147611144
Type: single nucleotide variant
Location: chr12:132625705 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2199: 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.Ile2199Phe Uncertain significance ★★ ⚠ same residue
POLE p.Ile2199Thr Uncertain significance ★ ⚠ same residue
POLE p.Ile2199Val Uncertain significance ★ ⚠ same residue
POLE p.Ile2199Met Uncertain significance ★ ⚠ 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

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-ile2199 (accessed [today's date]).

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