Is POLG p.Pro180= (c.540C>T) pathogenic?

POLG p.Pro180= (c.540C>T) is classified Likely benign in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-02). No allele count reported in gnomAD v4.1 (AN 1,576,748); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Pro180= (c.540C>T)?

POLG p.Pro180= (c.540C>T) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Pro180= (c.540C>T) in the general population?

POLG p.Pro180= (c.540C>T) is no allele count reported in gnomAD v4.1 (AN 1,576,748) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Pro180=

c.540C>T · rs2509274990 · VCV2825911

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,576,748)

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 5.5	GERP 1.5, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,576,748). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLG
Protein: p.Pro180=
Coding: c.540C>T
MANE Select: NM_002693
dbSNP: rs2509274990
Type: single nucleotide variant
Location: chr15:89333215 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 180: 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 p.Pro180Ser Uncertain significance ★★ ⚠ same residue
POLG p.Pro180Leu 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-pro180 (accessed [today's date]).

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