Is AARS2 p.Phe50Cys (c.149T>G) pathogenic?

AARS2 p.Phe50Cys (c.149T>G) is classified Pathogenic in AARS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-06-10). AlphaMissense: likely pathogenic (0.8303); Very rare (popmax 0.00017%, nfe); Associated with leukoencephalopathy, progressive, with ovarian failure.

What condition is associated with AARS2 p.Phe50Cys (c.149T>G)?

AARS2 p.Phe50Cys (c.149T>G) is associated with leukoencephalopathy, progressive, with ovarian failure (ClinVar).

How common is AARS2 p.Phe50Cys (c.149T>G) in the general population?

AARS2 p.Phe50Cys (c.149T>G) is very rare (popmax 0.00017%, 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.Phe50Cys (c.149T>G)?

AlphaMissense predicts likely pathogenic (score 0.8303) — an in-silico prediction, not a clinical call.

AARS2 p.Phe50Cys

c.149T>G · rs587777590 · VCV143045

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8303 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, progressive, with ovarian failure

Computational evidence

Protein change
AlphaMissense	0.8303	likely pathogenic ✓ concordant with ClinVar · top 8% in AARS2
REVEL	0.986	strongly pathogenic-leaning
SaProt	LLR -12.42	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	33.0	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 0.00017% European (non-Finnish) · 2/1,179,726 alleles

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

Overall 0.000137% 2/1,460,620 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.Phe50Cys
Coding: c.149T>G
MANE Select: NM_020745
dbSNP: rs587777590
Type: single nucleotide variant
Location: chr6:44313175 (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 50: a UniProt-annotated variant site (in lkenp; deleterious only under stress conditions)

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-phe50cys (accessed [today's date]).

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