Is AARS1 p.Ser249fs (c.743dup) pathogenic?

AARS1 p.Ser249fs (c.743dup) is classified Pathogenic in AARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-03). Very rare (popmax 0.00178%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with AARS1 p.Ser249fs (c.743dup)?

AARS1 p.Ser249fs (c.743dup) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Ser249fs (c.743dup) in the general population?

AARS1 p.Ser249fs (c.743dup) is very rare (popmax 0.00178%, nfe) (gnomAD).

AARS1 p.Ser249fs

c.743dup · VCV3605723

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00178%, 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 6 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.48	GERP -3.3, phastCons 0.031

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,024 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0015% 22/1,461,876 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,192
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ser249fs
Coding: c.743dup
MANE Select: NM_001605
Type: Duplication
Location: chr16:70270268 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 249: an α-helix

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 c.2722-28_2740dup Uncertain significance ★★ same condition
AARS1 p.Gln541fs Pathogenic ★ same condition
AARS1 p.Leu877fs Pathogenic ★ same condition
AARS1 p.Thr38fs Pathogenic ★ same condition
AARS1 p.Tyr497Ter Pathogenic ★ same condition
AARS1 p.Pro693_Val694insAspPro Uncertain significance ★ same condition
AARS1 c.144+12dup Benign ★ same condition
AARS1 c.2178-4dup Likely benign ★ 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-ser249fs (accessed [today's date]).

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