Is POLE p.Ser1139= (c.3417C>T) pathogenic?

POLE p.Ser1139= (c.3417C>T) is classified Likely benign in POLE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-02). Very rare (popmax 0.00668%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ser1139= (c.3417C>T)?

POLE p.Ser1139= (c.3417C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ser1139= (c.3417C>T) in the general population?

POLE p.Ser1139= (c.3417C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

POLE p.Ser1139=

c.3417C>T · rs762838377 · VCV383961

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.6	GERP -3.7
Overall
CADD	4.306	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,888 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00248% 40/1,613,944 alleles · very rare exomes 37/1,461,870 · genomes 3/152,074 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,963
South Asian	0.00329%	30,359
European (non-Finnish)	0.00263%	38,065
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,884

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.Ser1139=
Coding: c.3417C>T
MANE Select: NM_006231
dbSNP: rs762838377
Type: single nucleotide variant
Location: chr12:132657391 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1139: 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.Ser1139Arg Uncertain significance ★★ ⚠ same residue
POLE p.Ser1139Gly Uncertain significance ★ ⚠ same residue
POLE p.Ser1139Ile Uncertain significance ★ ⚠ same residue
POLE p.Ser1139Asn 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-ser1139 (accessed [today's date]).

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