GARS1

Chr 7AD

glycyl-tRNA synthetase 1

Also known as: CMT2D, DSMAV, GARS, GlyRS, HMN5, HMN5A, HMND5, SMAD1

NCBI Gene: 2617ENSG00000106105UniProt: P41250

This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, type 2DMIM #601472
AD
Neuronopathy, distal hereditary motor, autosomal dominant 5MIM #600794
AD
Spinal muscular atrophy, infantile, James typeMIM #619042
AD
380
ClinVar variants
9
Pathogenic / LP
0.31
pLI score
1
Active trials
Clinical Summary— GARS1
🧬
Gene-Disease Validity (ClinGen)
Charcot-Marie-Tooth disease type 2D · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 228 VUS of 380 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.40LOEUF
pLI 0.307
Z-score 4.46
OE 0.23 (0.14–0.40)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.20Z-score
OE missense 0.83 (0.76–0.91)
334 obs / 401.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.23 (0.14–0.40)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.76–0.91)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 9 / 39.1Missense obs/exp: 334 / 401.6Syn Z: -0.19

ClinVar Variant Classifications

380 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic5
VUS228
Likely Benign123
Benign14
Conflicting6
4
Pathogenic
5
Likely Pathogenic
228
VUS
123
Likely Benign
14
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
2
0
4
Likely Pathogenic
0
3
2
0
5
VUS
17
184
25
2
228
Likely Benign
0
5
58
60
123
Benign
0
0
14
0
14
Conflicting
—6
Total1719410162380

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GARS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Charcot-Marie-Tooth disease, type 2D

MIM #601472

Molecular basis of disorder known

Autosomal dominant

Neuronopathy, distal hereditary motor, autosomal dominant 5

MIM #600794

Molecular basis of disorder known

Autosomal dominant

Spinal muscular atrophy, infantile, James type

MIM #619042

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GARS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
Ferreira T et al.·J Neurol
2024
Glycyl-tRNA sequestration is a unifying mechanism underlying GARS1-associated peripheral neuropathy.
Mora N et al.·Nucleic Acids Res
2025Functional
Insights into phenotypic variability caused by GARS1 pathogenic variants.
Jiménez-Jiménez J et al.·Eur J Neurol
2024
Beyond translation: systematic insight of the multifaceted roles of GARS1 in cellular biology and disease.
Coronel Vargas G et al.·Cell Cycle
2026Review
Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes.
Meyer AP et al.·Hum Mutat
2022Case report
GARS-related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment.
Markovitz R et al.·Am J Med Genet A
2020
Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: A Korean cohort study.
Nam DE et al.·J Peripher Nerv Syst
2022Cohort
HDAC6 Inhibition Corrects Electrophysiological and Axonal Transport Deficits in a Human Stem Cell-Based Model of Charcot-Marie-Tooth Disease (Type 2D).
Smith AST et al.·Adv Biol (Weinh)
2022Functional
Infantile-onset CMT2D/dSMA-V in a Chinese family with parental germline mosaicism for a novel mutation in the GARS1 gene.
Huang Y et al.·Mol Genet Genomic Med
2022Case report
A familial form of Charcot-Marie-Tooth disease (type 2d) caused by a previously unreported variant in GARS1.
Varvara D et al.·J Neurogenet
2024Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Charcot-Marie-Tooth Disease Type 2D

Personalized Antisense Oligonucleotide for A Single Participant With GARS1 Gene Mutation Associated With Charcot-Marie-Tooth Disease Type 2D (CMT2D)

ENROLLING BY INVITATION
NCT07226297Phase PHASE1, PHASE2n-Lorem FoundationStarted 2025-10-27
nL-GARS1-001

External Resources

Links to major genomics databases and tools