Is POLE p.Thr2202= (c.6606G>A) pathogenic?

POLE p.Thr2202= (c.6606G>A) is classified Likely benign in POLE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0107%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Thr2202= (c.6606G>A)?

POLE p.Thr2202= (c.6606G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Thr2202= (c.6606G>A) in the general population?

POLE p.Thr2202= (c.6606G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

POLE p.Thr2202=

c.6606G>A · rs11146982 · VCV240607

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

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 -0.072	phastCons 0.18
Overall
CADD	4.065	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/75,072 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00118% 19/1,613,778 alleles · ultra-rare exomes 11/1,461,412 · genomes 8/152,366 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,384
East Asian	0.00668%	14,961
South Asian	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000424%	236,008

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.Thr2202=
Coding: c.6606G>A
MANE Select: NM_006231
dbSNP: rs11146982
Type: single nucleotide variant
Location: chr12:132625696 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2202: 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.Thr2202Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Thr2202Met Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Thr2202Ser Conflicting classifications of pathogenicity ★ ⚠ 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-thr2202 (accessed [today's date]).

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