Is POLE p.His1168fs (c.3501_3502insGGTCAAA) pathogenic?

POLE p.His1168fs (c.35013502insGGTCAAA) is classified Pathogenic in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). Very rare (popmax 0.000932%, nfe).

How common is POLE p.His1168fs (c.3501_3502insGGTCAAA) in the general population?

POLE p.His1168fs (c.3501_3502insGGTCAAA) is very rare (popmax 0.000932%, nfe) (gnomAD).

POLE p.His1168fs

c.3501_3502insGGTCAAA · rs1060500814 · VCV405692

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000932%, 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 29 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,179,938 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000752% 11/1,461,880 alleles · very rare

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.His1168fs
Coding: c.3501_3502insGGTCAAA
MANE Select: NM_006231
dbSNP: rs1060500814
Type: Insertion
Location: chr12:132657216 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1168: an α-helix; a UniProt-annotated variant site (in imagei)

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

Similar variants

POLE p.His1168Arg Uncertain significance ★ ⚠ same residue
POLE p.His1168Leu Uncertain significance ★ ⚠ same residue
POLE p.His1168Tyr Uncertain significance ★ ⚠ same residue
POLE c.1794+11_1794+12insA Likely benign ★★ same type
POLE p.Ala1260fs Pathogenic ★ same type
POLE p.Asp1214fs Pathogenic ★ same type
POLE p.Glu386fs Pathogenic ★ same type
POLE p.Glu767fs Pathogenic ★ 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-his1168fs (accessed [today's date]).

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