Is POLG p.Pro753Ser (c.2257C>T) pathogenic?

POLG p.Pro753Ser (c.2257C>T) is classified Uncertain significance in POLG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-22). AlphaMissense: likely pathogenic (0.8708); Very rare (popmax 0.00401%, afr); Associated with mitochondrial DNA depletion syndrome 4a.

How common is POLG p.Pro753Ser (c.2257C>T) in the general population?

POLG p.Pro753Ser (c.2257C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

What do computational predictors say about POLG p.Pro753Ser (c.2257C>T)?

AlphaMissense predicts likely pathogenic (score 0.8708) — an in-silico prediction, not a clinical call.

POLG p.Pro753Ser

Q: What condition is associated with POLG p.Pro753Ser (c.2257C>T)?

POLG p.Pro753Ser (c.2257C>T) is associated with mitochondrial DNA depletion syndrome 4a, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, mitochondrial DNA depletion syndrome 1 (ClinVar).

c.2257C>T · rs1446536384 · VCV1050879

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
AlphaMissense	0.8708	likely pathogenic
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -12.82	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00401% African / African-American · 3/74,786 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000187% 3/1,607,816 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.Pro753Ser
Coding: c.2257C>T
MANE Select: NM_002693
dbSNP: rs1446536384
Type: single nucleotide variant
Location: chr15:89323412 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB

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

Disease context

mitochondrial DNA depletion syndrome 4a — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Alpers-Huttenlocher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

POLG p.Pro753Arg Uncertain significance ★★ ⚠ same residue
POLG p.Pro753= Likely benign ★★ same residue
POLG p.Pro753Thr Uncertain significance ★ ⚠ same residue
POLG p.Pro753Leu 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

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-pro753ser (accessed [today's date]).

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