Is AARS2 p.Val195fs (c.584_585del) pathogenic?

AARS2 p.Val195fs (c.584585del) is classified Likely pathogenic in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-12). Associated with leukoencephalopathy, progressive, with ovarian failure.

What condition is associated with AARS2 p.Val195fs (c.584_585del)?

AARS2 p.Val195fs (c.584_585del) is associated with leukoencephalopathy, progressive, with ovarian failure (ClinVar).

How is CACH syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AARS2 p.Val195fs

c.584_585del · VCV4292427

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

leukoencephalopathy, progressive, with ovarian failure

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 5.1	GERP 0.91, phastCons 1

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

Variant & gene context

Gene: AARS2
Protein: p.Val195fs
Coding: c.584_585del
MANE Select: NM_020745
Type: Deletion
Location: chr6:44311158 (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

leukoencephalopathy, progressive, with ovarian failure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

AARS2 p.Gln261fs Pathogenic/Likely pathogenic ★★ same condition
AARS2 p.Gly647fs Pathogenic/Likely pathogenic ★★ same condition
AARS2 c.(759+1_760-1 Likely pathogenic ★ same condition
AARS2 p.Gly174fs Likely pathogenic ★ same condition
AARS2 p.Leu12_Arg14del Conflicting classifications of pathogenicity ★ 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-val195fs (accessed [today's date]).

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