Is POLE p.Ile238fs (c.711del) pathogenic?

POLE p.Ile238fs (c.711del) is classified Pathogenic in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). Very rare (popmax 0.000508%, nfe).

How common is POLE p.Ile238fs (c.711del) in the general population?

POLE p.Ile238fs (c.711del) is very rare (popmax 0.000508%, nfe) (gnomAD).

POLE p.Ile238fs

c.711del · rs2542178947 · VCV2856419

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,040 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,461,882 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.000508%	196,673

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile238fs
Coding: c.711del
MANE Select: NM_006231
dbSNP: rs2542178947
Type: Deletion
Location: chr12:132677587 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

POLE p.Ile238Leu Uncertain significance ★★ ⚠ same residue
POLE p.Ile238Phe Conflicting classifications of pathogenicity ★ same residue
POLE p.Ile238Thr Uncertain significance ★ ⚠ same residue
POLE p.Ile238Val Uncertain significance ★ ⚠ same residue
POLE p.Ile238= Likely benign ★ same residue
POLE c.5379-5_5384del Likely pathogenic ★★ same type
POLE p.Phe48fs Pathogenic/Likely pathogenic ★★ same type
POLE c.1359+4_1359+74del Uncertain significance ★★ same type

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-ile238fs (accessed [today's date]).

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