Is POLG p.Arg177= (c.531G>A) pathogenic?

POLG p.Arg177= (c.531G>A) is classified Likely benign in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-16). Very rare (popmax 8.62e-05%, nfe); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Arg177= (c.531G>A)?

POLG p.Arg177= (c.531G>A) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Arg177= (c.531G>A) in the general population?

POLG p.Arg177= (c.531G>A) is very rare (popmax 8.62e-05%, nfe) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Arg177=

c.531G>A · rs2509275031 · VCV2955312

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.62e-05%, nfe)

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	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.34	GERP 1.5, phastCons 0.98
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.62e-05% European (non-Finnish) · 1/1,159,822 alleles

Overall 7.01e-05% 1/1,426,656 alleles · very rare

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.Arg177=
Coding: c.531G>A
MANE Select: NM_001430120 · reported on NM_002693
dbSNP: rs2509275031
Type: single nucleotide variant
Location: chr15:89333224 (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-arg177 (accessed [today's date]).

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