Is POLG p.Lys331fs (c.991_992insG) pathogenic?

POLG p.Lys331fs (c.991992insG) is classified Pathogenic in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-22). Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Lys331fs (c.991_992insG)?

POLG p.Lys331fs (c.991_992insG) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Lys331fs

c.991_992insG · VCV3648962

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5	GERP 2.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: POLG
Protein: p.Lys331fs
Coding: c.991_992insG
MANE Select: NM_002693
Type: Insertion
Location: chr15:89328974 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 331: the 'disordered' region

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.Arg42_Gln43insArgGln Uncertain significance ★★ same condition
POLG p.Gln47_Gln48insHisGln Uncertain significance ★★ same condition
POLG p.Gln54fs Likely pathogenic ★ same condition
POLG p.Glu616Ter Likely pathogenic ★ same condition
POLG p.Arg1187fs Uncertain significance ★ same condition
POLG p.Arg42_Gln43insArgArgGln Uncertain significance ★ same condition
POLG p.Arg943delinsLeuSer Conflicting classifications of pathogenicity ★ same condition
POLG p.Gln51_Gln52insHis 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-lys331fs (accessed [today's date]).

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