KARS1

Chr 16AR

lysyl-tRNA synthetase 1

NCBI Gene: 3735ENSG00000065427UniProt: Q15046OMIM: 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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
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
15 unique Pathogenic / Likely Pathogenic· 100 VUS of 200 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 OE0.61 (0.42–0.91)
0≤0.351.4
Missense OE1.11 (1.02–1.21)
0≤0.61.4
Synonymous OE1.24
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

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

DN
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

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic10
VUS100
Likely Benign55
Conflicting3
5
Pathogenic
10
Likely Pathogenic
100
VUS
55
Likely Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
3
0
5
Likely Pathogenic
5
5
0
0
10
VUS
1
93
6
0
100
Likely Benign
0
0
24
31
55
Benign
0
0
0
0
0
Conflicting
—3
Total8983331173

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

View in ClinVar →

Protein Context — Lollipop Plot

KARS1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Hyperkinetic Movement Disorder in KARS1-Related Disease: An Illustrative Video-Recorded Case and Narrative Literature Review.
Ferasin V et al.·Neurol Int
2025Open AccessReview
Expansion of the phenotypic spectrum of KARS1-related disorders to include arthrogryposis multiplex congenita and summary of experiences with lysine supplementation.
Bejma TA et al.·Am J Med Genet A
2024
Antibody Deficiency in Patients with Biallelic KARS1 Mutations.
Saettini F et al.·J Clin Immunol
2023Cohort
Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish.
Lin SJ et al.·Genet Med
2021Open AccessFunctional
Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease.
Cappuccio G et al.·Hum Mutat
2021Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients