Is POLG p.Val503= (c.1509G>C) pathogenic?

POLG p.Val503= (c.1509G>C) is classified Likely benign in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). Very rare (popmax 0.00223%, eas); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Val503= (c.1509G>C)?

POLG p.Val503= (c.1509G>C) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Val503= (c.1509G>C) in the general population?

POLG p.Val503= (c.1509G>C) 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.Val503=

c.1509G>C · rs1018980768 · VCV1141169

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.49	donor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Overall
CADD	10.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,262 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
European (non-Finnish)	0.000169%	590,026

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.Val503=
Coding: c.1509G>C
MANE Select: NM_002693
dbSNP: rs1018980768
Type: single nucleotide variant
Location: chr15:89326988 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 503: 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.Val503Ala 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-val503 (accessed [today's date]).

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