Is POLG p.Arg374= (c.1122A>G) pathogenic?

POLG p.Arg374= (c.1122A>G) is classified Likely benign in POLG (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-23). Ultra-rare (popmax 0.0293%, afr); Associated with Inborn genetic diseases.

What condition is associated with POLG p.Arg374= (c.1122A>G)?

POLG p.Arg374= (c.1122A>G) is associated with Inborn genetic diseases, mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Arg374= (c.1122A>G) in the general population?

POLG p.Arg374= (c.1122A>G) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

POLG p.Arg374=

c.1122A>G · rs372759057 · VCV388514

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Conditions

Inborn genetic diseases

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 -6.3	GERP -4.8
Overall
CADD	1.398	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0293% African / African-American · 22/75,054 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00186% 30/1,614,150 alleles · ultra-rare exomes 21/1,461,836 · genomes 9/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,412
European (non-Finnish)	0.000678%	147,503

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.Arg374=
Coding: c.1122A>G
MANE Select: NM_002693
dbSNP: rs372759057
Type: single nucleotide variant
Location: chr15:89328733 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome 4a

Similar variants

POLG p.Arg374Ter Pathogenic ★★ same residue
POLG p.Arg374Gln 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-arg374 (accessed [today's date]).

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