Is POLG p.Pro324Ser (c.970C>T) pathogenic?

POLG p.Pro324Ser (c.970C>T) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 19 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0729); Ultra-rare (popmax 0.0646%, nfe); Associated with POLG-related disorder.

What condition is associated with POLG p.Pro324Ser (c.970C>T)?

POLG p.Pro324Ser (c.970C>T) is associated with POLG-related disorder, mitochondrial DNA depletion syndrome 4a, Charcot-Marie-Tooth disease (ClinVar).

How common is POLG p.Pro324Ser (c.970C>T) in the general population?

POLG p.Pro324Ser (c.970C>T) is ultra-rare (popmax 0.0646%, nfe) (gnomAD).

What do computational predictors say about POLG p.Pro324Ser (c.970C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

POLG p.Pro324Ser

c.970C>T · rs2307437 · VCV21320

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 19 submitters

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0646%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

POLG-related disorder

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.288	benign-leaning
SaProt	LLR -6.70	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 1.8	GERP -3.1, phastCons 0.006
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	9.28	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 0.0646% European (non-Finnish) · 762/1,180,044 alleles

Filtering AF 0.0607% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0592%

Overall 0.0509% 822/1,613,522 alleles · ultra-rare exomes 756/1,461,296 · genomes 66/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0646%	1,549
Remaining individualsnot grpmax-eligible	0.0577%	1,734
African / African-American	0.016%	6,244
Finnishnot grpmax-eligible	0.0125%	7,993
Admixed American	0.005%	20,003
South Asian	0.0011%	91,044

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.Pro324Ser
Coding: c.970C>T
MANE Select: NM_002693
dbSNP: rs2307437
Type: single nucleotide variant
Location: chr15:89328996 (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

Also linked: mitochondrial DNA depletion syndrome 4a Charcot-Marie-Tooth disease hereditary spastic paraplegia

Similar variants

POLG p.Pro324Arg Uncertain significance ★★ ⚠ same residue
POLG p.Pro324His Uncertain significance ★ ⚠ 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-pro324ser (accessed [today's date]).

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