PARS2

Chr 1AR

prolyl-tRNA synthetase 2, mitochondrial

NCBI Gene: 25973ENSG00000162396UniProt: Q7L3T8

Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the proline amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis. The reaction occurs in a two steps: proline is first activated by ATP to form Pro-AMP and then transferred to the acceptor end of tRNA(Pro)

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 75MIM #618437
AR
230
ClinVar variants
19
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PARS2
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 130 VUS of 230 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.
0.88LOEUF
pLI 0.004
Z-score 1.88
OE 0.45 (0.24–0.88)
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.
0.29Z-score
OE missense 0.95 (0.86–1.05)
266 obs / 279.5 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.0.45 (0.24–0.88)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.86–1.05)
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.0.91
0≤1.21.6
LoF obs/exp: 6 / 13.4Missense obs/exp: 266 / 279.5Syn Z: 0.78

ClinVar Variant Classifications

230 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic9
VUS130
Likely Benign65
Benign11
Conflicting5
10
Pathogenic
9
Likely Pathogenic
130
VUS
65
Likely Benign
11
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
9
0
10
Likely Pathogenic
0
2
7
0
9
VUS
3
115
11
1
130
Likely Benign
0
6
12
47
65
Benign
0
3
8
0
11
Conflicting
—5
Total41264748230

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

View in ClinVar →

Protein Context — Lollipop Plot

PARS2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PARS2-related developmental and epileptic encephalopathy with or without cardiomyopathy

definitive
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantframeshift variant NMD escaping

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 75

MIM #618437

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autozygome and high throughput confirmation of disease genes candidacy.
Maddirevula S et al.·Genet Med
2019
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike-and-wave activation in sleep.
Licchetta L et al.·Mol Genet Genomic Med
2024Review
Novel mutation in PARS2 revealed highly variable phenotype of developmental and epileptic encephalopathy-75.
Hu X et al.·Gene
2024
Clinical and molecular characteristics of newly reported mitochondrial disease entity caused by biallelic PARS2 mutations.
Ciara E et al.·J Hum Genet
2018Case report
Four pedigrees with aminoacyl-tRNA synthetase abnormalities.
Okamoto N et al.·Neurol Sci
2022
PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder.
Mizuguchi T et al.·J Hum Genet
2017
Activation of the integrated stress response contributes to developmental delay and seizures caused by mitochondrial prolyl-tRNA synthetase (PARS2) deficiency.
Xu M et al.·Redox Biol
2026
The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy.
Yin X et al.·J Hum Genet
2018Clinical trial
Intracranial calcifications simulating Aicardi-Goutières syndrome in PARS2-related mitochondrial disease.
Gerard A et al.·Am J Med Genet A
2024Case report
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