Is POLG p.Ser462Pro (c.1384T>C) pathogenic?

POLG p.Ser462Pro (c.1384T>C) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-09). AlphaMissense: likely pathogenic (0.9592); Absent from gnomAD v4.1; Associated with mitochondrial disease.

What condition is associated with POLG p.Ser462Pro (c.1384T>C)?

POLG p.Ser462Pro (c.1384T>C) is associated with mitochondrial disease (ClinVar).

How common is POLG p.Ser462Pro (c.1384T>C) in the general population?

POLG p.Ser462Pro (c.1384T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLG p.Ser462Pro (c.1384T>C)?

AlphaMissense predicts likely pathogenic (score 0.9592) — an in-silico prediction, not a clinical call.

POLG p.Ser462Pro

c.1384T>C · VCV3376898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9592 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.9592	likely pathogenic
REVEL	0.744	pathogenic-leaning
SaProt	LLR -9.62	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	24.6	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

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.Ser462Pro
Coding: c.1384T>C
MANE Select: NM_002693
Type: single nucleotide variant
Location: chr15:89327216 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 462: an α-helix

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

Disease context

mitochondrial disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLG p.Ser462Leu Uncertain significance ★★ ⚠ same residue
POLG p.Ser462= Conflicting classifications of pathogenicity ★ 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-ser462pro (accessed [today's date]).

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