Is POLG p.Val712fs (c.2134del) pathogenic?

POLG p.Val712fs (c.2134del) is classified Pathogenic in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-06). Absent from gnomAD; Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Val712fs (c.2134del)?

POLG p.Val712fs (c.2134del) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Val712fs (c.2134del) in the general population?

POLG p.Val712fs (c.2134del) is absent from gnomAD (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Val712fs

c.2134del · rs2509232156 · VCV2707445

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 12 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.59	GERP -3.6

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. 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.Val712fs
Coding: c.2134del
MANE Select: NM_002693
dbSNP: rs2509232156
Type: Deletion
Location: chr15:89323838 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB

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.Val712Met Uncertain significance ★★ ⚠ same residue
POLG p.Val712Leu Uncertain significance ★ ⚠ same residue
POLG c.3104+2_3104+5del Pathogenic/Likely pathogenic ★★ same condition
POLG c.3483-4_3497del Pathogenic/Likely pathogenic ★★ same condition
POLG c.3483-7_3509del Likely pathogenic ★★ same condition
POLG p.Ala839fs Pathogenic/Likely pathogenic ★★ same condition
POLG p.Arg227fs Pathogenic/Likely pathogenic ★★ same condition
POLG p.Gln663fs Pathogenic/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-val712fs (accessed [today's date]).

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