GARS1

Chr 7AD

glycyl-tRNA synthetase 1

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

NCBI Gene: 2617 ENSG00000106105 UniProt: P41250 OMIM: 600287

The protein functions as glycyl-tRNA synthetase, charging tRNAs with glycine as part of protein synthesis. Mutations cause autosomal dominant Charcot-Marie-Tooth disease type 2D, distal hereditary motor neuronopathy type 5, and infantile spinal muscular atrophy (James type). The pathogenic mechanism involves disruption of protein synthesis leading to selective motor and sensory neuron degeneration.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.403 OMIM phenotypes

Clinical Summary— GARS1

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease type 2D · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

30 unique Pathogenic / Likely Pathogenic· 457 VUS of 903 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GARS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.20Z-score

OE missense 0.83 (0.76–0.91)

334 obs / 401.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.14–0.40)

0≤0.351.4

Missense OE?0.83 (0.76–0.91)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 9 / 39.1Missense obs/exp: 334 / 401.6Syn Z: -0.19

This gene — mechanism propensity

0.5575th %ile

GOF

0.4776th %ile

LOF

0.4135th %ile

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports gain-of-function as the primary mechanism.

GOF1 literature citation · 90% of P/LP are missense

Literature Evidence

GOFInterestingly, these changes were more prominent in iNPCs of the dHMN-V patient carrying a dominant, probably gain-of-function GARS mutation (patient 1), suggesting that some neuropathy-associated mutations result in more severe or complex alteration of mitochondrial function in neurons.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29648643 ↗

ClinVar Variant Classifications

903 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic16

VUS457

Likely Benign269

Benign57

Conflicting68

Pathogenic

Likely Pathogenic

457

VUS

269

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	12	0	0	14
Likely Pathogenic	1	15	0	0	16
VUS	32	384	36	5	457
Likely Benign	0	13	114	142	269
Benign	0	5	46	6	57
Conflicting	—				68
Total	35	429	196	153	881

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap GARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →