Is AARS2 p.Arg722Gln (c.2165G>A) pathogenic?

AARS2 p.Arg722Gln (c.2165G>A) is classified Uncertain significance in AARS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1672); Ultra-rare (popmax 0.0156%, eas); Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Arg722Gln (c.2165G>A)?

AARS2 p.Arg722Gln (c.2165G>A) is associated with combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Arg722Gln (c.2165G>A) in the general population?

AARS2 p.Arg722Gln (c.2165G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about AARS2 p.Arg722Gln (c.2165G>A)?

AlphaMissense predicts likely benign (score 0.1672) — an in-silico prediction, not a clinical call.

AARS2 p.Arg722Gln

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.2165G>A · rs566667883 · VCV281937

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1672 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation defect type 8

Computational evidence

Protein change
AlphaMissense	0.1672	likely benign
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -12.90	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,882 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00223% 36/1,614,166 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
South Asian	0.00878%	11,384
African / African-American	0.004%	25,015
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.0011%	90,772

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.Arg722Gln
Coding: c.2165G>A
MANE Select: NM_020745
dbSNP: rs566667883
Type: single nucleotide variant
Location: chr6:44303156 (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 p.Arg722Trp Likely benign ★ ⚠ 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-arg722gln (accessed [today's date]).

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