KARS1

Chr 16AR

lysyl-tRNA synthetase 1

Also known as: CMTRIB, DEAPLE, DFNB89, KARS, KARS2, KRS, LEPID

NCBI Gene: 3735 ENSG00000065427 UniProt: Q15046 OMIM: 601421

Lysyl-tRNA synthetase catalyzes the attachment of lysine to its cognate tRNA and synthesizes the signaling molecule diadenosine tetraphosphate. Mutations cause autosomal recessive conditions including Charcot-Marie-Tooth disease, congenital or adult-onset deafness, and progressive leukoencephalopathy with infantile or later onset. The gene is not highly constrained against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm 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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.914 OMIM phenotypes

Clinical Summary— KARS1

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARLimited

Limited evidence — not for standalone diagnostic reporting

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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

34 unique Pathogenic / Likely Pathogenic· 246 VUS of 558 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.000

Z-score 1.96

OE 0.61 (0.42–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.73Z-score

OE missense 1.11 (1.02–1.21)

380 obs / 342.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.61 (0.42–0.91)

0≤0.351.4

Missense OE?1.11 (1.02–1.21)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 18 / 29.5Missense obs/exp: 380 / 342.1Syn Z: -2.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKARS1-related deafnessOTHERAR

strongKARS1-related leukoencephalopathy with or without deafnessLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7036th %ile

GOF

0.6051th %ile

LOF

0.3258th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

558 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic17

VUS246

Likely Benign185

Benign41

Conflicting25

Pathogenic

Likely Pathogenic

246

VUS

185

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	7	1	0	17
Likely Pathogenic	7	10	0	0	17
VUS	2	226	16	2	246
Likely Benign	0	6	94	85	185
Benign	0	3	33	5	41
Conflicting	—				25
Total	18	252	144	92	531

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap KARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →