Is POLG p.Pro1239= (c.3717A>G) pathogenic?

POLG p.Pro1239= (c.3717A>G) is classified Likely benign in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-13). Very rare (popmax 0.00223%, eas); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Pro1239= (c.3717A>G)?

POLG p.Pro1239= (c.3717A>G) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Pro1239= (c.3717A>G) in the general population?

POLG p.Pro1239= (c.3717A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Pro1239=

c.3717A>G · rs764634689 · VCV1930986

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

mitochondrial DNA depletion syndrome 4a

⚠ 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 -3.1	GERP -4.2
Overall
CADD	1.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,611,754 alleles · very rare exomes 8/1,459,396 · genomes 0/152,358 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,436
European (non-Finnish)	0.000509%	196,291

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.Pro1239=
Coding: c.3717A>G
MANE Select: NM_002693
dbSNP: rs764634689
Type: single nucleotide variant
Location: chr15:89316754 (GRCh38)

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

Disease context

mitochondrial DNA depletion syndrome 4a — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alpers-Huttenlocher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Europe)

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-pro1239 (accessed [today's date]).

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