Is AARS2 p.Tyr565Ter (c.1695C>G) pathogenic?

AARS2 p.Tyr565Ter (c.1695C>G) is classified Likely pathogenic in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-14). Absent from gnomAD v4.1; Associated with leukoencephalopathy, progressive, with ovarian failure.

What condition is associated with AARS2 p.Tyr565Ter (c.1695C>G)?

AARS2 p.Tyr565Ter (c.1695C>G) is associated with leukoencephalopathy, progressive, with ovarian failure (ClinVar).

How common is AARS2 p.Tyr565Ter (c.1695C>G) in the general population?

AARS2 p.Tyr565Ter (c.1695C>G) is absent from gnomAD v4.1 (gnomAD).

How is CACH syndrome inherited?

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

AARS2 p.Tyr565Ter

c.1695C>G · rs774607571 · VCV1707535

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

leukoencephalopathy, progressive, with ovarian failure

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.5	GERP -4.5
Overall
CADD	28.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AARS2
Protein: p.Tyr565Ter
Coding: c.1695C>G
MANE Select: NM_020745
dbSNP: rs774607571
Type: single nucleotide variant
Location: chr6:44304702 (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.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
AARS2 p.Ala386Val Uncertain significance ★★ ⚠ same condition
AARS2 p.Arg101His Uncertain significance ★★ ⚠ same condition
AARS2 p.Gly965Arg 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-tyr565ter (accessed [today's date]).

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