Is POLE p.Ile1326= (c.3978C>T) pathogenic?

POLE p.Ile1326= (c.3978C>T) is classified Likely benign in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). Very rare (popmax 0.00246%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ile1326= (c.3978C>T)?

POLE p.Ile1326= (c.3978C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ile1326= (c.3978C>T) in the general population?

POLE p.Ile1326= (c.3978C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

POLE p.Ile1326=

c.3978C>T · rs755659438 · VCV383382

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

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 0.23	GERP -3.4, phastCons 0.62
Overall
CADD	5.375	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,180,054 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00186% 30/1,613,570 alleles · very rare exomes 27/1,461,328 · genomes 3/152,242 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,692
African / African-American	0.00133%	74,940

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.Ile1326=
Coding: c.3978C>T
MANE Select: NM_006231
dbSNP: rs755659438
Type: single nucleotide variant
Location: chr12:132649333 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1326: 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.Ile1326Val Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ile1326Leu Uncertain significance ★ ⚠ same residue
POLE p.Ile1326Thr 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
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-ile1326 (accessed [today's date]).

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