Is POLE p.Ala2040Val (c.6117_6119delinsTGT) pathogenic?

POLE p.Ala2040Val (c.61176119delinsTGT) is classified Likely benign in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-06). Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala2040Val (c.6117_6119delinsTGT)?

POLE p.Ala2040Val (c.6117_6119delinsTGT) is associated with hereditary neoplastic syndrome (ClinVar).

POLE p.Ala2040Val

c.6117_6119delinsTGT · VCV4862298

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

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 · substitutions only
Constraint at this position
Conservation	phyloP 0.024
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic

Variant & gene context

Gene: POLE
Protein: p.Ala2040Val
Coding: c.6117_6119delinsTGT
MANE Select: NM_006231
Type: Indel
Location: chr12:132632681 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2040: a UniProt-annotated variant site (in imagei); a UniProt-annotated variant site (in)

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.Ala2040Glu Uncertain significance ★★ ⚠ same residue
POLE p.Ala2040= Likely benign ★★ same residue
POLE p.Ala2040Leu Uncertain significance ★ same residue
POLE c.6531+4_6531+10delinsAGAAGG Uncertain significance ★★ same condition
POLE p.Ala1224Leu Uncertain significance ★★ same condition
POLE p.Asp1954Phe Uncertain significance ★★ same condition
POLE p.Glu926Gln Uncertain significance ★★ same condition
POLE p.Gly1191Ser 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-ala2040val (accessed [today's date]).

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