Is AARS2 p.Phe131del (c.387CTT[1]) pathogenic?

AARS2 p.Phe131del (c.387CTT[1]) is classified Pathogenic/Likely pathogenic in AARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-01). Very rare (popmax 0.00136%, nfe); Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Phe131del (c.387CTT[1])?

AARS2 p.Phe131del (c.387CTT[1]) is associated with combined oxidative phosphorylation defect type 8, leukoencephalopathy, progressive, with ovarian failure (ClinVar).

How common is AARS2 p.Phe131del (c.387CTT[1]) in the general population?

AARS2 p.Phe131del (c.387CTT[1]) is very rare (popmax 0.00136%, nfe) (gnomAD).

AARS2 p.Phe131del

Q: How is Combined oxidative phosphorylation defect type 8 inherited?

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

c.387CTT[1] · rs1561943859 · VCV1322076

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

combined oxidative phosphorylation defect type 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	GERP 1.1, phastCons 1
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,180,052 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,614,126 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)grpmax	0.00136%	73,753

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe131del
Coding: c.387CTT[1]
MANE Select: NM_020745
dbSNP: rs1561943859
Type: Microsatellite
Location: chr6:44312115 (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 131: a UniProt-annotated variant site (found in patient with leukoencephalopathy; uncertain significance)

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

Disease context

combined oxidative phosphorylation defect type 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: leukoencephalopathy, progressive, with ovarian failure

For Combined oxidative phosphorylation defect type 8 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AARS2 c.2146-2A>G Pathogenic/Likely pathogenic ★★ same condition
AARS2 c.2255+1G>A Pathogenic ★★ same condition
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.Cys218fs Pathogenic ★★ same condition
AARS2 p.Gln261fs 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-phe131del (accessed [today's date]).

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