Is AARS1 p.Glu337Lys (c.1009G>A) pathogenic?

AARS1 p.Glu337Lys (c.1009G>A) is classified Pathogenic in AARS1 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-12-17). AlphaMissense: likely pathogenic (0.9304); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with AARS1 p.Glu337Lys (c.1009G>A)?

AARS1 p.Glu337Lys (c.1009G>A) is associated with Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease axonal type 2N (ClinVar).

How common is AARS1 p.Glu337Lys (c.1009G>A) in the general population?

AARS1 p.Glu337Lys (c.1009G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AARS1 p.Glu337Lys (c.1009G>A)?

AlphaMissense predicts likely pathogenic (score 0.9304) — an in-silico prediction, not a clinical call.

AARS1 p.Glu337Lys

c.1009G>A · rs2152160733 · VCV1323797

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9304 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.9304	likely pathogenic ✓ concordant with ClinVar
REVEL	0.519	indeterminate
SaProt	LLR -13.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AARS1
Protein: p.Glu337Lys
Coding: c.1009G>A
MANE Select: NM_001605
dbSNP: rs2152160733
Type: single nucleotide variant
Location: chr16:70268333 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 337: 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

Also linked: Charcot-Marie-Tooth disease axonal type 2N

Similar variants

AARS1 c.2177+1G>A Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg13Ter Pathogenic ★★ same condition
AARS1 p.Arg246Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg329Cys Likely pathogenic ★★ same condition
AARS1 p.Arg329His Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg330Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg333Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg598Ter 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/aars1-p-glu337lys (accessed [today's date]).

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