Is POLE p.Pro1610fs (c.4826dup) pathogenic?

POLE p.Pro1610fs (c.4826dup) is classified Pathogenic in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). Very rare (popmax 0.000169%, nfe).

How common is POLE p.Pro1610fs (c.4826dup) in the general population?

POLE p.Pro1610fs (c.4826dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

POLE p.Pro1610fs

c.4826dup · rs2138535602 · VCV1402986

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, 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 37 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.52	phastCons 0.026

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,038 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,406 alleles · very rare exomes 2/1,461,048 · genomes 0/152,358 · joint denominator

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.Pro1610fs
Coding: c.4826dup
MANE Select: NM_006231
dbSNP: rs2138535602
Type: Duplication
Location: chr12:132642631 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1610: 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.Pro1610Thr Uncertain significance ★★ ⚠ same residue
POLE p.Pro1610Ser Uncertain significance ★ ⚠ same residue
POLE c.802-2dup Uncertain significance ★★ same type
POLE c.802-7_818dup Uncertain significance ★★ same type
POLE p.Asp1026_Leu1032dup Uncertain significance ★★ same type
POLE p.Gln1950_Glu1956dup Uncertain significance ★★ same type
POLE p.Glu1963_Asn1971dup Uncertain significance ★★ same type
POLE p.Ile1864dup 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-pro1610fs (accessed [today's date]).

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