Is AARS2 p.Cys218fs (c.647dup) pathogenic?

AARS2 p.Cys218fs (c.647dup) is classified Pathogenic in AARS2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-15). Ultra-rare (popmax 0.0122%, nfe); Associated with AARS2-related disorder.

What condition is associated with AARS2 p.Cys218fs (c.647dup)?

AARS2 p.Cys218fs (c.647dup) is associated with AARS2-related disorder, combined oxidative phosphorylation defect type 8, pulmonary hypoplasia (ClinVar).

How common is AARS2 p.Cys218fs (c.647dup) in the general population?

AARS2 p.Cys218fs (c.647dup) is ultra-rare (popmax 0.0122%, nfe) (gnomAD).

AARS2 p.Cys218fs

c.647dup · rs587777589 · VCV143044

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, nfe)

Conditions

AARS2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.77	GERP -1.3, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% European (non-Finnish) · 144/1,180,048 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00994%

Overall 0.00917% 148/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0122%	8,195
Admixed American	0.00333%	30,006
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Cys218fs
Coding: c.647dup
MANE Select: NM_020745
dbSNP: rs587777589
Type: Duplication
Location: chr6:44311095 (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

Also linked: combined oxidative phosphorylation defect type 8 pulmonary hypoplasia

Similar variants

AARS2 p.Ile884fs Likely pathogenic ★ same condition
AARS2 p.Cys218Ser Uncertain significance ★ ⚠ same residue
AARS2 c.2146-2A>G Pathogenic/Likely pathogenic ★★ same condition
AARS2 c.2255+1G>A Pathogenic ★★ same condition
AARS2 c.2598+1G>T Pathogenic/Likely 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

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-cys218fs (accessed [today's date]).

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