Is POLE p.Val2234fs (c.6699del) pathogenic?

POLE p.Val2234fs (c.6699del) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Val2234fs (c.6699del)?

POLE p.Val2234fs (c.6699del) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Val2234fs (c.6699del) in the general population?

POLE p.Val2234fs (c.6699del) is no gnomAD frequency available for this variant (gnomAD).

POLE p.Val2234fs

c.6699del · rs1869467642 · VCV840286

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (48 of 49, 48 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. 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.Val2234fs
Coding: c.6699del
MANE Select: NM_006231
dbSNP: rs1869467642
Type: Deletion
Location: chr12:132624953 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2234: 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.Val2234= Likely benign ★★ same residue
POLE c.1359+4_1359+74del Uncertain significance ★★ same condition
POLE c.206_211delCCGAGA Uncertain significance ★★ same condition
POLE c.3459+4del Uncertain significance ★★ same condition
POLE p.Ala1288_Leu1295del Uncertain significance ★★ same condition
POLE p.Gln1950_Glu1956del Uncertain significance ★★ same condition
POLE p.Glu1965_Glu1969del Uncertain significance ★★ same condition
POLE p.Glu223_Arg231del 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-val2234fs (accessed [today's date]).

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