Is AARS2 p.Thr979= (c.2937C>G) pathogenic?

AARS2 p.Thr979= (c.2937C>G) is classified Conflicting classifications of pathogenicity in AARS2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-16). Rare (popmax 0.143%, eas); Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Thr979= (c.2937C>G)?

AARS2 p.Thr979= (c.2937C>G) is associated with combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Thr979= (c.2937C>G) in the general population?

AARS2 p.Thr979= (c.2937C>G) is rare (popmax 0.143%, eas) (gnomAD).

AARS2 p.Thr979=

Q: How is Combined oxidative phosphorylation defect type 8 inherited?

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

c.2937C>G · rs200778121 · VCV912181

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.143%, eas)

Conditions

combined oxidative phosphorylation defect type 8

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 2.8	GERP -0.058, phastCons 1
Overall
CADD	7.383	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.143% East Asian · 64/44,888 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.104%

Overall 0.0044% 71/1,614,104 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.143%	701
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.000254%	393,349

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: AARS2
Protein: p.Thr979=
Coding: c.2937C>G
MANE Select: NM_020745
dbSNP: rs200778121
Type: single nucleotide variant
Location: chr6:44300568 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.05 · 3 PDB
Residue 979: an α-helix

Full AARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation defect type 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 8 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AARS2 c.2146-2A>G Pathogenic/Likely pathogenic ★★ same condition
AARS2 c.2255+1G>A Pathogenic ★★ same condition
AARS2 p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Arg521Ter Pathogenic ★★ same condition
AARS2 p.Arg592Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Arg958Ter Pathogenic/Likely pathogenic ★★ same condition
AARS2 p.Thr782Ile Likely pathogenic ★★ same condition
AARS2 c.*718C>A 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/aars2-p-thr979 (accessed [today's date]).

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