Is POLG p.Pro514Ser (c.1540C>T) pathogenic?

POLG p.Pro514Ser (c.1540C>T) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: likely benign (0.0896); Absent from gnomAD v4.1.

How common is POLG p.Pro514Ser (c.1540C>T) in the general population?

POLG p.Pro514Ser (c.1540C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLG p.Pro514Ser (c.1540C>T)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

POLG p.Pro514Ser

c.1540C>T · rs756376617 · VCV429290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	17.65	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.Pro514Ser
Coding: c.1540C>T
MANE Select: NM_002693
dbSNP: rs756376617
Type: single nucleotide variant
Location: chr15:89326957 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 514: the 'disordered' region; the 'accessory-interacting determinant' region

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

Similar variants

POLG p.Pro514Ala Uncertain significance ★★ ⚠ same residue
POLG p.Pro514Arg Uncertain significance ★ ⚠ same residue
POLG p.Pro514= Likely benign ★ same residue
POLG c.3643+2T>C Pathogenic ★★★ same type
POLG p.Ala1105Pro Likely pathogenic ★★★ same type
POLG p.Arg1096Cys Likely pathogenic ★★★ same type
POLG p.Asp1184Asn Pathogenic ★★★ same type
POLG p.Gln1175Ter Likely pathogenic ★★★ same type

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-pro514ser (accessed [today's date]).

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