Is POLE p.Ser1340= (c.4020C>T) pathogenic?

POLE p.Ser1340= (c.4020C>T) is classified Likely benign in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-12). No allele count reported in gnomAD v4.1 (AN 1,611,940); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ser1340= (c.4020C>T)?

POLE p.Ser1340= (c.4020C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ser1340= (c.4020C>T) in the general population?

POLE p.Ser1340= (c.4020C>T) is no allele count reported in gnomAD v4.1 (AN 1,611,940) (gnomAD).

POLE p.Ser1340=

c.4020C>T · rs961050579 · VCV540850

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,611,940)

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 2.5	GERP 0.51, phastCons 1
Overall
CADD	4.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,611,940). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLE
Protein: p.Ser1340=
Coding: c.4020C>T
MANE Select: NM_006231
dbSNP: rs961050579
Type: single nucleotide variant
Location: chr12:132649058 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1340: a turn; 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.Ser1340Gly Uncertain significance ★★ ⚠ same residue
POLE p.Ser1340Ile 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
POLE c.1226+3A>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-ser1340 (accessed [today's date]).

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