Is POLE p.Ser1380Ter (c.4138_4139insAGT) pathogenic?

POLE p.Ser1380Ter (c.41384139insAGT) is classified Pathogenic in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). Absent from gnomAD.

How common is POLE p.Ser1380Ter (c.4138_4139insAGT) in the general population?

POLE p.Ser1380Ter (c.4138_4139insAGT) is absent from gnomAD (gnomAD).

POLE p.Ser1380Ter

c.4138_4139insAGT · rs2042349678 · VCV1040262

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 32 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1

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.Ser1380Ter
Coding: c.4138_4139insAGT
MANE Select: NM_006231
dbSNP: rs2042349678
Type: Insertion
Location: chr12:132648939 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1380: 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.Ser1380= Likely benign ★★ same residue
POLE p.Ser1380Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ser1380Pro 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-ser1380ter (accessed [today's date]).

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