KARS1

Chr 16

lysyl-tRNA synthetase 1

NCBI Gene: 3735ENSG00000065427UniProt: Q15046

Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA (PubMed:18029264, PubMed:18272479, PubMed:9278442). When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages (PubMed:15851690). Catalyzes the synthesis of the signaling molecule diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of the complex between HINT1 and MITF and the concomitant activation of MITF transcriptional activity (PubMed:14975237, PubMed:19524539, PubMed:23159739, PubMed:5338216)

Primary Disease Associations & Inheritance

UniProtCharcot-Marie-Tooth disease, recessive intermediate B
UniProtDeafness, autosomal recessive, 89
UniProtDeafness, congenital, and adult-onset progressive leukoencephalopathy
UniProtLeukoencephalopathy, progressive, infantile-onset, with or without deafness
603
ClinVar variants
33
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— KARS1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 233 VUS of 603 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.91LOEUF
pLI 0.000
Z-score 1.96
OE 0.61 (0.42–0.91)
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.
-0.73Z-score
OE missense 1.11 (1.02–1.21)
380 obs / 342.1 exp
Tolerant

Tolerant to missense variation

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.0.61 (0.42–0.91)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.11 (1.02–1.21)
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.1.24
0≤1.21.6
LoF obs/exp: 18 / 29.5Missense obs/exp: 380 / 342.1Syn Z: -2.13

ClinVar Variant Classifications

603 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic14
VUS233
Likely Benign164
Benign31
Conflicting11
19
Pathogenic
14
Likely Pathogenic
233
VUS
164
Likely Benign
31
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
4
13
0
19
Likely Pathogenic
2
8
4
0
14
VUS
1
208
22
2
233
Likely Benign
0
4
86
74
164
Benign
0
0
28
3
31
Conflicting
—11
Total522415379472

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.

Gene2Phenotype Curations

KARS1-related deafness

limited
ARUndeterminedAltered Gene Product Structure
Dev. DisordersEar
G2P ↗
missense variantinframe deletioninframe insertion

KARS1-related leukoencephalopathy with or without deafness

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel Cases of Non-Syndromic Hearing Impairment Caused by Pathogenic Variants in Genes Encoding Mitochondrial Aminoacyl-tRNA Synthetases.
Domínguez-Ruiz M et al.·Genes (Basel)
2024Cohort
Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish.
Lin SJ et al.·Genet Med
2021Functional
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
2021Case report
Antibody Deficiency in Patients with Biallelic KARS1 Mutations.
Saettini F et al.·J Clin Immunol
2023Cohort
Leopard-like retinopathy and severe early-onset portal hypertension expand the phenotype of KARS1-related syndrome: a case report.
Peluso F et al.·BMC Med Genomics
2021Case report
The complex relationship between MITF and the immune system: a Melanoma ImmunoTherapy (response) Factor?
Ballotti R et al.·Mol Cancer
2020Review
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
2024Case report
Genetic landscape in undiagnosed patients with syndromic hearing loss revealed by whole exome sequencing and phenotype similarity search.
Mutai H et al.·Hum Genet
2025Cohort
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