Is POLG2 p.Leu289Val (c.865C>G) pathogenic?

POLG2 p.Leu289Val (c.865C>G) is classified Conflicting classifications of pathogenicity in POLG2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.113); Rare (popmax 0.231%, mid).

How common is POLG2 p.Leu289Val (c.865C>G) in the general population?

POLG2 p.Leu289Val (c.865C>G) is rare (popmax 0.231%, mid) (gnomAD).

What do computational predictors say about POLG2 p.Leu289Val (c.865C>G)?

AlphaMissense predicts likely benign (score 0.113) — an in-silico prediction, not a clinical call.

POLG2 p.Leu289Val

c.865C>G · rs530697513 · VCV1576352

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.113 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.231%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.113	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -5.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.98 · regional, not allelic
Overall
CADD	19.34	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.231% Middle Eastern · 14/6,062 alleles

Filtering AF 0.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.00874% 141/1,613,892 alleles · rare exomes 133/1,461,550 · genomes 8/152,342 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.231%	433
South Asian	0.0472%	2,118
Remaining individualsnot grpmax-eligible	0.016%	6,249
Admixed American	0.0117%	8,575
European (non-Finnish)	0.00542%	18,434
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
African / African-American	0.00266%	37,533

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: POLG2
Protein: p.Leu289Val
Coding: c.865C>G
MANE Select: NM_007215
dbSNP: rs530697513
Type: single nucleotide variant
Location: chr17:64490900 (GRCh38)

Full POLG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/polg2-p-leu289val (accessed [today's date]).

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