Is POLG p.Pro324Arg (c.971C>G) pathogenic?

POLG p.Pro324Arg (c.971C>G) is classified Uncertain significance in POLG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-21). AlphaMissense: likely benign (0.0626); Very rare (popmax 0.000508%, nfe); Associated with Inborn genetic diseases.

What condition is associated with POLG p.Pro324Arg (c.971C>G)?

POLG p.Pro324Arg (c.971C>G) is associated with Inborn genetic diseases, mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Pro324Arg (c.971C>G) in the general population?

POLG p.Pro324Arg (c.971C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about POLG p.Pro324Arg (c.971C>G)?

AlphaMissense predicts likely benign (score 0.0626) — an in-silico prediction, not a clinical call.

POLG p.Pro324Arg

c.971C>G · rs764492040 · VCV1060224

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0626 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0626	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -7.14	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 -0.89	GERP -4.8
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	0.539	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

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,046 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,552 alleles · very rare exomes 5/1,461,326 · genomes 1/152,226 · joint denominator

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.Pro324Arg
Coding: c.971C>G
MANE Select: NM_002693
dbSNP: rs764492040
Type: single nucleotide variant
Location: chr15:89328995 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 324: the 'disordered' region; a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome 4a

Similar variants

POLG p.Pro324His Uncertain significance ★ ⚠ same residue
POLG p.Pro324Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
POLG p.Pro324Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLG p.Pro324= Likely benign ★ 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

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-pro324arg (accessed [today's date]).

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