Is POLG2 p.Pro244fs (c.729_730del) pathogenic?

POLG2 p.Pro244fs (c.729730del) is classified Pathogenic in POLG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). Associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4.

POLG2 p.Pro244fs

Q: What condition is associated with POLG2 p.Pro244fs (c.729_730del)?

POLG2 p.Pro244fs (c.729_730del) is associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (ClinVar).

Q: How is Autosomal dominant progressive external ophthalmoplegia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.729_730del · VCV3375474

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4

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 3 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1

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

Variant & gene context

Gene: POLG2
Protein: p.Pro244fs
Coding: c.729_730del
MANE Select: NM_007215
Type: Deletion
Location: chr17:64492732 (GRCh38)
Gene constraint: LOEUF 1.156 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.73 · 38 PDB

Full POLG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant progressive external ophthalmoplegia (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

POLG2 p.Pro244Ser Uncertain significance ★ ⚠ same residue
POLG2 p.Pro244Thr Uncertain significance ★ ⚠ same residue
POLG2 p.Ala9Val Uncertain significance ★★ ⚠ same condition
POLG2 p.Arg122Ser Uncertain significance ★★ same condition
POLG2 p.Glu123Lys Uncertain significance ★★ ⚠ same condition
POLG2 p.Gly188Arg Uncertain significance ★★ ⚠ same condition
POLG2 p.Phe439Leu Uncertain significance ★★ ⚠ same condition
POLG2 p.Pro245Leu 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/polg2-p-pro244fs (accessed [today's date]).

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