Is POLG p.Ser240Pro (c.718T>C) pathogenic?

POLG p.Ser240Pro (c.718T>C) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-10). AlphaMissense: ambiguous (0.4093); Absent from gnomAD v4.1; Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Ser240Pro (c.718T>C)?

POLG p.Ser240Pro (c.718T>C) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Ser240Pro (c.718T>C) in the general population?

POLG p.Ser240Pro (c.718T>C) is absent from gnomAD v4.1 (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.Ser240Pro (c.718T>C)?

AlphaMissense predicts ambiguous (score 0.4093) — an in-silico prediction, not a clinical call.

POLG p.Ser240Pro

c.718T>C · rs2141806695 · VCV1377975

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4093 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
AlphaMissense	0.4093	ambiguous
REVEL	0.453	indeterminate
SaProt	LLR -9.65	tolerated
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.3	GERP 2.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	24.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLG
Protein: p.Ser240Pro
Coding: c.718T>C
MANE Select: NM_002693
dbSNP: rs2141806695
Type: single nucleotide variant
Location: chr15:89330218 (GRCh38)

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)

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-ser240pro (accessed [today's date]).

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