PARS2

Chr 1AR

prolyl-tRNA synthetase 2, mitochondrial

Also known as: DEE75, EIEE75, MT-PRORS, proRS

NCBI Gene: 25973 ENSG00000162396 UniProt: Q7L3T8 OMIM: 612036

This protein is a mitochondrial aminoacyl-tRNA synthetase that catalyzes the attachment of proline to its corresponding tRNA molecule, essential for mitochondrial protein synthesis. Mutations cause developmental and epileptic encephalopathy 75, which follows an autosomal recessive inheritance pattern. The condition involves early-onset seizures and developmental impairment affecting the central nervous system.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a putative member of the class II family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of proline to tRNA molecules. Mutations have been found in this gene in some patients with Alpers syndrome. [provided by RefSeq, Mar 2015]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.881 OMIM phenotype

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

8 unique Pathogenic / Likely Pathogenic· 128 VUS of 218 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?

0.88LOEUF

pLI 0.004

Z-score 1.88

OE 0.45 (0.24–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.29Z-score

OE missense 0.95 (0.86–1.05)

266 obs / 279.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.24–0.88)

0≤0.351.4

Missense OE?0.95 (0.86–1.05)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 6 / 13.4Missense obs/exp: 266 / 279.5Syn Z: 0.78

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePARS2-related developmental and epileptic encephalopathy with or without cardiomyopathyOTHERAR

This gene — mechanism propensity

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

0.75top 25%

GOF

0.4973th %ile

LOF

0.2775th %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

218 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic7

VUS128

Likely Benign64

Benign11

Conflicting5

Pathogenic

Likely Pathogenic

128

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	5	2	0	0	7
VUS	7	118	2	1	128
Likely Benign	0	6	9	49	64
Benign	0	3	8	0	11
Conflicting	—				5
Total	13	129	19	50	216

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap PARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →