Is POLG p.Ser511Arg (c.1533C>G) pathogenic?

POLG p.Ser511Arg (c.1533C>G) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely benign (0.1862); Absent from gnomAD v4.1; Associated with POLG-related disorder.

What condition is associated with POLG p.Ser511Arg (c.1533C>G)?

POLG p.Ser511Arg (c.1533C>G) is associated with POLG-related disorder (ClinVar).

How common is POLG p.Ser511Arg (c.1533C>G) in the general population?

POLG p.Ser511Arg (c.1533C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLG p.Ser511Arg (c.1533C>G)?

AlphaMissense predicts likely benign (score 0.1862) — an in-silico prediction, not a clinical call.

POLG p.Ser511Arg

c.1533C>G · rs1225524682 · VCV2633356

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1862 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

POLG-related disorder

Computational evidence

Protein change
AlphaMissense	0.1862	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.5	GERP 0.99, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	18.58	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLG
Protein: p.Ser511Arg
Coding: c.1533C>G
MANE Select: NM_002693
dbSNP: rs1225524682
Type: single nucleotide variant
Location: chr15:89326964 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 511: the 'disordered' region; the 'accessory-interacting determinant' region; a UniProt-annotated variant site (in peoa1)

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

Disease context

POLG-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLG p.Ser511Thr Uncertain significance ★★ ⚠ same residue
POLG p.Ser511= Uncertain significance ★ same residue
POLG p.Ser511Asn Pathogenic ⚠ same residue
POLG c.1171-2A>G Likely pathogenic ★★ same condition
POLG c.1433+2T>C Pathogenic/Likely pathogenic ★★ same condition
POLG c.2480+1G>T Pathogenic/Likely pathogenic ★★ same condition
POLG c.3104+3A>T Pathogenic ★★ same condition
POLG c.855+1G>C 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-ser511arg (accessed [today's date]).

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