Is AARS2 p.Leu893= (c.2679C>T) pathogenic?

AARS2 p.Leu893= (c.2679C>T) is classified Conflicting classifications of pathogenicity in AARS2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-30). Ultra-rare (popmax 0.0615%, sas); Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Leu893= (c.2679C>T)?

AARS2 p.Leu893= (c.2679C>T) is associated with combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Leu893= (c.2679C>T) in the general population?

AARS2 p.Leu893= (c.2679C>T) is ultra-rare (popmax 0.0615%, sas) (gnomAD).

AARS2 p.Leu893=

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.2679C>T · rs766642839 · VCV357058

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0615%, sas)

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	<0.2	all four deltas below 0.2 · G>C here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.23	GERP -0.22, phastCons 0.94
Overall
CADD	4.769	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0615% South Asian · 56/91,072 alleles

Filtering AF 0.0486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.044%

Overall 0.0118% 191/1,613,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.372%	269
South Asiangrpmax	0.0615%	1,626
Remaining individualsnot grpmax-eligible	0.016%	6,248
European (non-Finnish)	0.00127%	78,670

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu893=
Coding: c.2679C>T
MANE Select: NM_020745
dbSNP: rs766642839
Type: single nucleotide variant
Location: chr6:44301384 (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 893: 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 p.Leu893Pro Uncertain significance ★ ⚠ same residue
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

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-leu893 (accessed [today's date]).

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