Is AARS2 p.Arg756Cys (c.2266C>T) pathogenic?

AARS2 p.Arg756Cys (c.2266C>T) is classified Uncertain significance in AARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-09). AlphaMissense: likely benign (0.0996); Ultra-rare (popmax 0.0233%, amr); Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Arg756Cys (c.2266C>T)?

AARS2 p.Arg756Cys (c.2266C>T) is associated with combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Arg756Cys (c.2266C>T) in the general population?

AARS2 p.Arg756Cys (c.2266C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about AARS2 p.Arg756Cys (c.2266C>T)?

AlphaMissense predicts likely benign (score 0.0996) — an in-silico prediction, not a clinical call.

AARS2 p.Arg756Cys

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.2266C>T · rs753324375 · VCV357060

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0996 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined oxidative phosphorylation defect type 8

Computational evidence

Protein change
AlphaMissense	0.0996	likely benign
REVEL	0.444	indeterminate
SaProt	LLR -11.65	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.9, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	27.7	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 0.0233% Admixed American · 14/59,994 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00725% 117/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.101%	987
Admixed Americangrpmax	0.0233%	4,285
Remaining individualsnot grpmax-eligible	0.0096%	10,413
European (non-Finnish)	0.00559%	17,879
African / African-American	0.00133%	74,920

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.Arg756Cys
Coding: c.2266C>T
MANE Select: NM_020745
dbSNP: rs753324375
Type: single nucleotide variant
Location: chr6:44302900 (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.Arg756His 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-arg756cys (accessed [today's date]).

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