EPRS1

Chr 1AR

glutamyl-prolyl-tRNA synthetase 1

Also known as: EARS, EPRS, GLUPRORS, HLD15, PARS, PIG32, QARS, QPRS

NCBI Gene: 2058 ENSG00000136628 UniProt: P07814 OMIM: 138295

The protein encoded by EPRS1 is a multifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species in the cytoplasm. Mutations cause hypomyelinating leukodystrophy 15 through autosomal recessive inheritance. The pathogenic mechanism likely involves disrupted protein synthesis due to impaired tRNA charging with these essential amino acids.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a multifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. Alternative splicing has been observed for this gene, but the full-length nature and biological validity of the variant have not been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.511 OMIM phenotype

Clinical Summary— EPRS1

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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

19 unique Pathogenic / Likely Pathogenic· 272 VUS of 535 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.000

Z-score 5.28

OE 0.37 (0.28–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.60Z-score

OE missense 0.84 (0.79–0.90)

669 obs / 795.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.28–0.51)

0≤0.351.4

Missense OE?0.84 (0.79–0.90)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 31 / 82.9Missense obs/exp: 669 / 795.6Syn Z: -1.54

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongEPRS1-related hypomyelinating leukodystrophyLOFAR

This gene — mechanism propensity

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

0.6161th %ile

GOF

0.6345th %ile

LOF

0.4037th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

535 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic4

VUS272

Likely Benign165

Benign34

Conflicting8

Pathogenic

Likely Pathogenic

272

VUS

165

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	4	0	0	15
Likely Pathogenic	3	1	0	0	4
VUS	1	260	11	0	272
Likely Benign	0	17	64	84	165
Benign	0	8	16	10	34
Conflicting	—				8
Total	15	290	91	94	498

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap EPRS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →