Is POLG p.Ala172= (c.516G>A) pathogenic?

POLG p.Ala172= (c.516G>A) is classified Likely benign in POLG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-08). Very rare (popmax 0.0023%, eas); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Ala172= (c.516G>A)?

POLG p.Ala172= (c.516G>A) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Ala172= (c.516G>A) in the general population?

POLG p.Ala172= (c.516G>A) is very rare (popmax 0.0023%, eas) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Ala172=

c.516G>A · rs1028326668 · VCV619379

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0023%, eas)

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 2.5	GERP 1.7, phastCons 1
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0023% East Asian · 1/43,474 alleles

Filtering AF 0.000186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000571% 9/1,576,690 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0023%	43,474
African / African-American	0.00135%	73,860
South Asian	0.00115%	87,208
European (non-Finnish)	0.000517%	193,240

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.Ala172=
Coding: c.516G>A
MANE Select: NM_001430120 · reported on NM_002693
dbSNP: rs1028326668
Type: single nucleotide variant
Location: chr15:89333239 (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-ala172 (accessed [today's date]).

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