YARS1

Chr 1ADAR

tyrosyl-tRNA synthetase 1

Also known as: CMTDIC, IMNEPD2, TYRRS, YARS, YRS, YTS

NCBI Gene: 8565ENSG00000134684UniProt: P54577

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Tyrosyl-tRNA synthetase belongs to the class I tRNA synthetase family. Cytokine activities have also been observed for the human tyrosyl-tRNA synthetase, after it is split into two parts, an N-terminal fragment that harbors the catalytic site and a C-terminal fragment found only in the mammalian enzyme. The N-terminal fragment is an interleukin-8-like cytokine, whereas the released C-terminal fragment is an EMAP II-like cytokine. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, dominant intermediate CMIM #608323
AD
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2MIM #619418
AR
581
ClinVar variants
14
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— YARS1
🧬
Gene-Disease Validity (ClinGen)
Charcot-Marie-Tooth disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 340 VUS of 581 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.62LOEUF
pLI 0.001
Z-score 3.05
OE 0.37 (0.23–0.62)
Tolerant

Typical tolerance to LoF variation

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.
1.14Z-score
OE missense 0.81 (0.73–0.90)
228 obs / 281.7 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.0.37 (0.23–0.62)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.73–0.90)
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.1.10
0≤1.21.6
LoF obs/exp: 10 / 27.2Missense obs/exp: 228 / 281.7Syn Z: -0.85

ClinVar Variant Classifications

581 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic7
VUS340
Likely Benign188
Benign21
Conflicting18
7
Pathogenic
7
Likely Pathogenic
340
VUS
188
Likely Benign
21
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
2
4
0
7
Likely Pathogenic
0
6
1
0
7
VUS
25
264
48
3
340
Likely Benign
0
6
88
94
188
Benign
0
0
19
2
21
Conflicting
—18
Total2627816099581

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

View in ClinVar →

Protein Context — Lollipop Plot

YARS1 · 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, dominant intermediate C

MIM #608323

Molecular basis of disorder known

Autosomal dominant

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2

MIM #619418

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — YARS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype.
Averdunk L et al.·J Mol Med (Berl)
2021Review
A missense, loss-of-function YARS1 variant in a patient with proximal-predominant motor neuropathy.
Forrest ME et al.·Cold Spring Harb Mol Case Stud
2022Case report
[Expression of YARS1 in hepatocellular carcinoma and its prognostic effect].
Hu LH et al.·Zhonghua Gan Zang Bing Za Zhi
2025
Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: A Korean cohort study.
Nam DE et al.·J Peripher Nerv Syst
2022Cohort
Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation.
Høyer H et al.·BMC Neurol
2022
Distal hereditary motor neuropathy due to a novel YARS1 gene pathogenic variant.
Llauradó A et al.·Muscle Nerve
2023Case report
Weighted gene co-expression network analysis reveals key stromal prognostic markers in pancreatic cancer.
Mantini G et al.·Sci Rep
2024
Novel partial loss-of-function variants in the tyrosyl-tRNA synthetase 1 (YARS1) gene involved in multisystem disease.
Estève C et al.·Eur J Med Genet
2021Case report
[NEXT-GENERATION SEQUENCING PERFORMED IN PATIENTS RAISING THE SUSPICION OF AN INBORN ERROR OF METABOLISM UNCOVERED A HOMOZYGOUS VARIANT IN YARS1 ALLOWING A NOVEL THERAPEUTIC TRIAL].
Nasser Samra N et al.·Harefuah
2023Cohort
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools