Is AARS2 p.Ser466= (c.1398C>T) pathogenic?

AARS2 p.Ser466= (c.1398C>T) is classified Benign/Likely benign in AARS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-03). Rare (popmax 0.766%, afr); Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Ser466= (c.1398C>T)?

AARS2 p.Ser466= (c.1398C>T) is associated with combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Ser466= (c.1398C>T) in the general population?

AARS2 p.Ser466= (c.1398C>T) is rare (popmax 0.766%, afr) (gnomAD).

AARS2 p.Ser466=

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.1398C>T · rs146711725 · VCV136229

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.766%, afr)

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	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.9	GERP -3.3
Overall
CADD	0.321	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.766% African / African-American · 575/75,034 alleles

Filtering AF 0.714% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.694%

Overall 0.0495% 799/1,614,138 alleles · rare exomes 466/1,461,868 · genomes 333/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.766%	130
Admixed American	0.11%	909
Remaining individualsnot grpmax-eligible	0.0688%	1,454
Middle Eastern	0.033%	3,031
South Asian	0.00988%	10,120
European (non-Finnish)	0.00856%	11,683
East Asian	0.00446%	22,437
Finnishnot grpmax-eligible	0.00156%	64,026

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.Ser466=
Coding: c.1398C>T
MANE Select: NM_020745
dbSNP: rs146711725
Type: single nucleotide variant
Location: chr6:44305689 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.05 · 3 PDB

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-ser466 (accessed [today's date]).

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