Is POLG p.Arg722= (c.2166T>C) pathogenic?

POLG p.Arg722= (c.2166T>C) is classified Likely benign in POLG (ClinVar, Single submitter, 2 submitters; last evaluated 2024-07-16). Ultra-rare (popmax 0.0264%, sas); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Arg722= (c.2166T>C)?

POLG p.Arg722= (c.2166T>C) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Arg722= (c.2166T>C) in the general population?

POLG p.Arg722= (c.2166T>C) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Arg722=

c.2166T>C · rs767669686 · VCV1547165

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

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 assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.92	GERP -0.58, phastCons 0.13
Overall
CADD	2.492	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0264% South Asian · 24/90,974 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00155% 25/1,608,858 alleles · ultra-rare exomes 25/1,456,546 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,791
European (non-Finnish)	8.51e-05%	1,175,183

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.Arg722=
Coding: c.2166T>C
MANE Select: NM_002693
dbSNP: rs767669686
Type: single nucleotide variant
Location: chr15:89323503 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB

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.Arg722Leu Uncertain significance ★★ ⚠ same residue
POLG p.Arg722Pro Uncertain significance ★★ ⚠ same residue
POLG p.Arg722His Benign/Likely benign ★★ same residue
POLG p.Arg722Cys 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

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-arg722 (accessed [today's date]).

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