Is POLG p.Leu157= (c.471G>C) pathogenic?

POLG p.Leu157= (c.471G>C) is classified Likely benign in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). Very rare (popmax 0.00116%, sas); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Leu157= (c.471G>C)?

POLG p.Leu157= (c.471G>C) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Leu157= (c.471G>C) in the general population?

POLG p.Leu157= (c.471G>C) is very rare (popmax 0.00116%, sas) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Leu157=

c.471G>C · rs745813477 · VCV1114552

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00116%, sas)

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -3.5
Overall
CADD	0.372	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00116% South Asian · 1/86,388 alleles

Overall 0.000128% 2/1,557,806 alleles · very rare exomes 2/1,405,436 · genomes 0/152,370 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00116%	86,388
European (non-Finnish)	8.69e-05%	1,150,398

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.Leu157=
Coding: c.471G>C
MANE Select: NM_002693
dbSNP: rs745813477
Type: single nucleotide variant
Location: chr15:89333284 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 157: an α-helix

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 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
POLG c.3483-14T>C Uncertain significance ★★★ same condition
POLG c.3643+48A>G Uncertain significance ★★★ 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-leu157 (accessed [today's date]).

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