Is POLG p.Arg996= (c.2988G>A) pathogenic?

POLG p.Arg996= (c.2988G>A) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-26). Absent from gnomAD v4.1; Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Arg996= (c.2988G>A)?

POLG p.Arg996= (c.2988G>A) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Arg996= (c.2988G>A) in the general population?

POLG p.Arg996= (c.2988G>A) is absent from gnomAD v4.1 (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Arg996=

c.2988G>A · rs2055360184 · VCV885041

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -0.2	GERP 0.15, phastCons 0.27
Overall
CADD	8.511	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLG
Protein: p.Arg996=
Coding: c.2988G>A
MANE Select: NM_002693
dbSNP: rs2055360184
Type: single nucleotide variant
Location: chr15:89319344 (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.Arg996Gln Uncertain significance ★★ ⚠ same residue
POLG p.Arg996Trp Uncertain significance ★★ ⚠ same residue
POLG p.Arg996Gly 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

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-arg996 (accessed [today's date]).

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