Is AARS1 p.Phe345fs (c.1032del) pathogenic?

AARS1 p.Phe345fs (c.1032del) is classified Pathogenic in AARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-21). Very rare (popmax 8.47e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with AARS1 p.Phe345fs (c.1032del)?

AARS1 p.Phe345fs (c.1032del) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Phe345fs (c.1032del) in the general population?

AARS1 p.Phe345fs (c.1032del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

AARS1 p.Phe345fs

c.1032del · rs2507013974 · VCV1903181

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Charcot-Marie-Tooth disease type 2

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 8 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,868 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: AARS1
Protein: p.Phe345fs
Coding: c.1032del
MANE Select: NM_001605
dbSNP: rs2507013974
Type: Deletion
Location: chr16:70268310 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 345: a turn

Full AARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AARS1 p.Phe345Ile Uncertain significance ★ ⚠ same residue
AARS1 p.Phe345= Likely benign ★ same residue
AARS1 p.Tyr109_Lys111delinsTer Pathogenic/Likely pathogenic ★★ same condition
AARS1 c.334-13_334-9del Likely benign ★★ same condition
AARS1 c.334-6_338del Likely pathogenic ★ same condition
AARS1 c.962+1del Pathogenic ★ same condition
AARS1 p.Ala347fs Pathogenic ★ same condition
AARS1 p.Arg333_Tyr334insTer 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/aars1-p-phe345fs (accessed [today's date]).

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