Is POLG p.Ala703= (c.2109C>A) pathogenic?

POLG p.Ala703= (c.2109C>A) is classified Benign/Likely benign in POLG (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Low-frequency (popmax 3.41%, afr); Associated with POLG-related disorder.

How common is POLG p.Ala703= (c.2109C>A) in the general population?

POLG p.Ala703= (c.2109C>A) is low-frequency (popmax 3.41%, afr) (gnomAD).

POLG p.Ala703=

Q: What condition is associated with POLG p.Ala703= (c.2109C>A)?

POLG p.Ala703= (c.2109C>A) is associated with POLG-related disorder, mitochondrial DNA depletion syndrome 4a, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (ClinVar).

c.2109C>A · rs2307429 · VCV129990

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.41%, afr)

Conditions

POLG-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP -0.55, phastCons 0.97
Overall
CADD	8.286	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.41% African / African-American · 2,560/75,008 alleles

Filtering AF 3.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.26%

Overall 0.202% 3,256/1,614,044 alleles · low-frequency exomes 1,825/1,461,764 · genomes 1,431/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.41%	29
Middle Eastern	0.544%	184
Ashkenazi Jewishnot grpmax-eligible	0.348%	287
Admixed American	0.287%	349
Remaining individualsnot grpmax-eligible	0.28%	357
European (non-Finnish)	0.0169%	5,929
South Asian	0.0121%	8,280
Finnishnot grpmax-eligible	0.00468%	21,346

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: POLG
Protein: p.Ala703=
Coding: c.2109C>A
MANE Select: NM_002693
dbSNP: rs2307429
Type: single nucleotide variant
Location: chr15:89323863 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB

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

Disease context

Also linked: mitochondrial DNA depletion syndrome 4a progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 mitochondrial DNA depletion syndrome 1 sensory ataxic neuropathy, dysarthria, and ophthalmoparesis mitochondrial DNA depletion syndrome 4b progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

Similar variants

POLG p.Ala703Val Uncertain significance ★★ ⚠ same residue
POLG c.3643+2T>C Pathogenic ★★★ same condition
POLG p.Ala1105Pro Likely pathogenic ★★★ same condition
POLG p.Arg1096Cys Likely pathogenic ★★★ same condition
POLG p.Asp1184Asn Pathogenic ★★★ same condition
POLG p.Gln1175Ter Likely pathogenic ★★★ same condition
POLG p.Lys1191Asn Likely pathogenic ★★★ same condition
POLG c.3483-14T>C 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/polg-p-ala703 (accessed [today's date]).

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