Is AARS2 p.Lys953fs (c.2855dup) pathogenic?

AARS2 p.Lys953fs (c.2855dup) is classified Uncertain significance in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with AARS2 p.Lys953fs (c.2855dup)?

AARS2 p.Lys953fs (c.2855dup) is associated with Cardiovascular phenotype (ClinVar).

How common is AARS2 p.Lys953fs (c.2855dup) in the general population?

AARS2 p.Lys953fs (c.2855dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

AARS2 p.Lys953fs

c.2855dup · VCV3894766

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (22 of 22) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.8	GERP -1.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,012 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,456 alleles · very rare

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.Lys953fs
Coding: c.2855dup
MANE Select: NM_020745
Type: Duplication
Location: chr6:44300649 (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 953: a β-strand

Full AARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AARS2 p.Ala740Thr Uncertain significance ★★ ⚠ same condition
AARS2 p.Arg769Cys Uncertain significance ★★ ⚠ same condition
AARS2 p.Glu314del Uncertain significance ★★ same condition
AARS2 p.His225Tyr Uncertain significance ★★ ⚠ same condition
AARS2 p.Ile224Leu Uncertain significance ★★ ⚠ same condition
AARS2 p.Ile766Ser Uncertain significance ★★ ⚠ same condition
AARS2 p.Leu118Val Uncertain significance ★★ ⚠ same condition
AARS2 p.Leu538Met 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-lys953fs (accessed [today's date]).

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