Is AARS2 p.Thr129Pro (c.385A>C) pathogenic?

AARS2 p.Thr129Pro (c.385A>C) is classified Likely pathogenic in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-12). AlphaMissense: likely pathogenic (0.7925); Very rare (popmax 0.000169%, nfe); Associated with leukoencephalopathy, progressive, with ovarian failure.

What condition is associated with AARS2 p.Thr129Pro (c.385A>C)?

AARS2 p.Thr129Pro (c.385A>C) is associated with leukoencephalopathy, progressive, with ovarian failure (ClinVar).

How common is AARS2 p.Thr129Pro (c.385A>C) in the general population?

AARS2 p.Thr129Pro (c.385A>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is CACH syndrome inherited?

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

What do computational predictors say about AARS2 p.Thr129Pro (c.385A>C)?

AlphaMissense predicts likely pathogenic (score 0.7925) — an in-silico prediction, not a clinical call.

AARS2 p.Thr129Pro

c.385A>C · rs773257559 · VCV1027411

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, progressive, with ovarian failure

Computational evidence

Protein change
AlphaMissense	0.7925	likely pathogenic ✓ concordant with ClinVar · top 10% in AARS2
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -15.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	29.0	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 0.000169% European (non-Finnish) · 2/1,180,032 alleles

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

Overall 0.000124% 2/1,614,188 alleles · very rare exomes 2/1,461,888 · genomes 0/152,300 · joint denominator

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.Thr129Pro
Coding: c.385A>C
MANE Select: NM_020745
dbSNP: rs773257559
Type: single nucleotide variant
Location: chr6:44312122 (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-thr129pro (accessed [today's date]).

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