Is POLG p.Arg386Pro (c.1157G>C) pathogenic?

POLG p.Arg386Pro (c.1157G>C) is classified Likely pathogenic in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-24). AlphaMissense: likely pathogenic (0.9631); Very rare (popmax 0.000254%, nfe); Associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1.

What condition is associated with POLG p.Arg386Pro (c.1157G>C)?

POLG p.Arg386Pro (c.1157G>C) is associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, mitochondrial DNA depletion syndrome 4a, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (ClinVar).

How common is POLG p.Arg386Pro (c.1157G>C) in the general population?

POLG p.Arg386Pro (c.1157G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about POLG p.Arg386Pro (c.1157G>C)?

AlphaMissense predicts likely pathogenic (score 0.9631) — an in-silico prediction, not a clinical call.

POLG p.Arg386Pro

Q: How is Autosomal recessive progressive external ophthalmoplegia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1157G>C · VCV3578004

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Computational evidence

Protein change
AlphaMissense	0.9631	likely pathogenic ✓ concordant with ClinVar
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -15.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	26.8	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 0.000254% European (non-Finnish) · 3/1,180,038 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,796 alleles · very rare

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.Arg386Pro
Coding: c.1157G>C
MANE Select: NM_002693
Type: single nucleotide variant
Location: chr15:89328698 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 386: an α-helix

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

Disease context

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome 4a sensory ataxic neuropathy, dysarthria, and ophthalmoparesis mitochondrial DNA depletion syndrome 4b progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

For Autosomal recessive progressive external ophthalmoplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

POLG p.Arg386His Uncertain significance ★★ ⚠ same residue
POLG p.Arg386Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
POLG p.Arg386Gly 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

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-arg386pro (accessed [today's date]).

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