Is POLG p.Pro765Thr (c.2293C>A) pathogenic?

POLG p.Pro765Thr (c.2293C>A) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-09-16). AlphaMissense: likely pathogenic (0.9617); Very rare (popmax 8.48e-05%, nfe); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Pro765Thr (c.2293C>A)?

POLG p.Pro765Thr (c.2293C>A) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Pro765Thr (c.2293C>A) in the general population?

POLG p.Pro765Thr (c.2293C>A) is very rare (popmax 8.48e-05%, nfe) (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.Pro765Thr (c.2293C>A)?

AlphaMissense predicts likely pathogenic (score 0.9617) — an in-silico prediction, not a clinical call.

POLG p.Pro765Thr

c.2293C>A · rs1003442806 · VCV458703

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
AlphaMissense	0.9617	likely pathogenic
REVEL	0.971	strongly pathogenic-leaning
SaProt	LLR -15.46	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	26.5	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 8.48e-05% European (non-Finnish) · 1/1,179,920 alleles

Overall 0.000137% 2/1,461,136 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,442
European (non-Finnish)grpmax	8.48e-05%	1,179,920

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro765Thr
Coding: c.2293C>A
MANE Select: NM_002693
dbSNP: rs1003442806
Type: single nucleotide variant
Location: chr15:89322875 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 765: a β-strand

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

For Alpers-Huttenlocher syndrome (Orphanet):

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

Similar variants

POLG p.Pro765= Likely benign ★★ same residue
POLG p.Pro765Leu 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
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-pro765thr (accessed [today's date]).

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