Is POLG p.Val266= (c.798G>T) pathogenic?

POLG p.Val266= (c.798G>T) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-03-01). Rare (popmax 0.131%, mid); Associated with POLG-related disorder.

What condition is associated with POLG p.Val266= (c.798G>T)?

POLG p.Val266= (c.798G>T) is associated with POLG-related disorder, mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Val266= (c.798G>T) in the general population?

POLG p.Val266= (c.798G>T) is rare (popmax 0.131%, mid) (gnomAD).

POLG p.Val266=

c.798G>T · rs143631183 · VCV138769

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.131%, mid)

Conditions

POLG-related disorder

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 0.49	GERP 0.3, phastCons 0.99
Overall
CADD	7.042	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.131% Middle Eastern · 8/6,084 alleles

Filtering AF 0.0887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0809%

Overall 0.0351% 567/1,613,934 alleles · rare exomes 489/1,461,706 · genomes 78/152,228 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.131%	761
Admixed American	0.11%	909
Remaining individualsnot grpmax-eligible	0.0912%	1,096
African / African-American	0.0614%	1,629
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,278
European (non-Finnish)	0.0314%	3,189
South Asian	0.00659%	15,182
Finnishnot grpmax-eligible	0.00157%	63,866

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.Val266=
Coding: c.798G>T
MANE Select: NM_002693
dbSNP: rs143631183
Type: single nucleotide variant
Location: chr15:89330138 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 266: a β-strand

Full POLG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: mitochondrial DNA depletion syndrome 4a

Similar variants

POLG p.Val266Leu Uncertain significance ★ ⚠ same residue
POLG p.Val266Ala 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-val266 (accessed [today's date]).

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