Is POLG p.Pro829= (c.2487C>T) pathogenic?

POLG p.Pro829= (c.2487C>T) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.033%, mid); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Pro829= (c.2487C>T)?

POLG p.Pro829= (c.2487C>T) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Pro829= (c.2487C>T) in the general population?

POLG p.Pro829= (c.2487C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Pro829=

c.2487C>T · rs147563527 · VCV288698

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.3	GERP -4
Overall
CADD	0.219	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00404%

Overall 0.00502% 81/1,613,668 alleles · ultra-rare exomes 74/1,461,426 · genomes 7/152,242 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0112%	8,927
East Asian	0.00669%	14,957
Admixed American	0.00666%	15,005
European (non-Finnish)	0.00551%	18,148

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.Pro829=
Coding: c.2487C>T
MANE Select: NM_002693
dbSNP: rs147563527
Type: single nucleotide variant
Location: chr15:89321847 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 829: a β-strand

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)

Similar variants

POLG p.Pro829Ser Uncertain significance ★★ ⚠ same residue
POLG p.Pro829Thr 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

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-pro829 (accessed [today's date]).

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