POLG2 p.Ser423=

Q: Is POLG2 p.Ser423= (c.1269C>T) pathogenic?

POLG2 p.Ser423= (c.1269C>T) is classified Benign in POLG2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 15.4%, amr) — too common for a highly-penetrant pathogenic allele; Associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4.

Q: What condition is associated with POLG2 p.Ser423= (c.1269C>T)?

POLG2 p.Ser423= (c.1269C>T) is associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (ClinVar).

Q: How common is POLG2 p.Ser423= (c.1269C>T) in the general population?

POLG2 p.Ser423= (c.1269C>T) is common (popmax 15.4%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Autosomal dominant progressive external ophthalmoplegia inherited?

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

c.1269C>T · rs61733782 · VCV138784

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 15.4%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.55	GERP -1.4, phastCons 0.99
Overall
CADD	2.365	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 15.4% Admixed American · 9,206/59,724 alleles

Filtering AF 15.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 15%

Overall 6.18% 97,132/1,572,444 alleles · common exomes 84,616/1,420,340 · genomes 12,516/152,104 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	15.4%	6
African / African-American	10.9%	9
Finnishnot grpmax-eligible	6.17%	16
Remaining individualsnot grpmax-eligible	5.81%	17
European (non-Finnish)	5.71%	18
Ashkenazi Jewishnot grpmax-eligible	5.32%	19
Middle Eastern	4.76%	21
South Asian	4.19%	24
Amishnot grpmax-eligible	3.51%	29
East Asian	3.4%	29

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: POLG2
Protein: p.Ser423=
Coding: c.1269C>T
MANE Select: NM_007215
dbSNP: rs61733782
Type: single nucleotide variant
Location: chr17:64480312 (GRCh38)

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

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-ser423 (accessed [today's date]).

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