YARS1

Chr 1ADAR

tyrosyl-tRNA synthetase 1

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

NCBI Gene: 8565 ENSG00000134684 UniProt: P54577 OMIM: 603623

The protein catalyzes the aminoacylation of tRNA with tyrosine and also functions as a cytokine when cleaved into N-terminal and C-terminal fragments. Mutations cause autosomal dominant Charcot-Marie-Tooth disease intermediate type C and autosomal recessive infantile-onset multisystem neurologic, endocrine, and pancreatic disease. The pathogenic mechanism likely involves disruption of protein synthesis through impaired tRNA charging and potential loss of cytokine signaling functions.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.622 OMIM phenotypes

Clinical Summary— YARS1

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 358 VUS of 665 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — YARS1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.001

Z-score 3.05

OE 0.37 (0.23–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.14Z-score

OE missense 0.81 (0.73–0.90)

228 obs / 281.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.23–0.62)

0≤0.351.4

Missense OE?0.81 (0.73–0.90)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 10 / 27.2Missense obs/exp: 228 / 281.7Syn Z: -0.85

This gene — mechanism propensity

0.6161th %ile

GOF

0.6151th %ile

LOF

0.3550th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

665 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic9

VUS358

Likely Benign204

Benign40

Conflicting29

Pathogenic

Likely Pathogenic

358

VUS

204

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	5	0	0	6
Likely Pathogenic	1	8	0	0	9
VUS	37	279	39	3	358
Likely Benign	0	6	94	104	204
Benign	0	1	36	3	40
Conflicting	—				29
Total	39	299	169	110	646

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap YARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →