Is POLG p.Arg40Pro (c.119G>C) pathogenic?

POLG p.Arg40Pro (c.119G>C) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0631); Very rare (popmax 0.00205%, nfe); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Arg40Pro (c.119G>C)?

POLG p.Arg40Pro (c.119G>C) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Arg40Pro (c.119G>C) in the general population?

POLG p.Arg40Pro (c.119G>C) is very rare (popmax 0.00205%, 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.Arg40Pro (c.119G>C)?

AlphaMissense predicts likely benign (score 0.0631) — an in-silico prediction, not a clinical call.

POLG p.Arg40Pro

c.119G>C · VCV3691001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00205%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 4a

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0631	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.29	GERP -1, phastCons 0.02
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	9.058	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 0.00205% European (non-Finnish) · 24/1,169,590 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00117%

Overall 0.00151% 24/1,586,442 alleles · very rare exomes 24/1,434,572 · genomes 0/151,870 · 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.Arg40Pro
Coding: c.119G>C
MANE Select: NM_002693
Type: single nucleotide variant
Location: chr15:89333636 (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-arg40pro (accessed [today's date]).

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