Developmental and epileptic encephalopathy, 75

Summary

Developmental and epileptic encephalopathy, 75 (MONDO:0032752) is a disease caused by PARS2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PARS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 75
Mondo ID	MONDO:0032752
OMIM	618437
DOID	DOID:0112211
UMLS	C5193099
MedGen	1684253
GARD	0016352
Is cancer (heuristic)	no

Also known as: DEE75 · developmental and epileptic encephalopathy 75 · EIEE75 · EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 75 · epileptic encephalopathy, early infantile, 75

Data availability: 20 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 75

Related subtypes (104): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 91, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 74, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 53, developmental and epileptic encephalopathy, 54, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 64, developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

20 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 4 conflicting classifications of pathogenicity, 3 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
183148	NM_152268.4(PARS2):c.1130dup (p.Pro377_Lys378insTer)	PARS2	Pathogenic	no assertion criteria provided
3067934	NM_152268.4(PARS2):c.886C>T (p.Gln296Ter)	PARS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3767223	NM_152268.4(PARS2):c.877C>G (p.Pro293Ala)	PARS2	Likely pathogenic	criteria provided, single submitter
4086062	NM_152268.4(PARS2):c.1271A>T (p.Asp424Val)	PARS2	Likely pathogenic	criteria provided, single submitter
1086760	NM_152268.4(PARS2):c.1075G>T (p.Asp359Tyr)	PARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183149	NM_152268.4(PARS2):c.836C>T (p.Ser279Leu)	PARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432121	NM_152268.4(PARS2):c.283G>A (p.Val95Ile)	PARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
632566	NM_152268.4(PARS2):c.1091C>G (p.Pro364Arg)	PARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1500391	NM_152268.4(PARS2):c.1129C>G (p.Pro377Ala)	PARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1698984	NM_152268.4(PARS2):c.874T>C (p.Cys292Arg)	PARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2228634	NM_152268.4(PARS2):c.294G>A (p.Met98Ile)	PARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065467	NM_152268.4(PARS2):c.287G>A (p.Arg96His)	PARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382531	NM_152268.4(PARS2):c.1308del (p.Gly437fs)	PARS2	Uncertain significance	criteria provided, single submitter
3899361	NM_152268.4(PARS2):c.32T>A (p.Leu11Ter)	PARS2	Uncertain significance	criteria provided, single submitter
4292565	NM_152268.4(PARS2):c.499G>A (p.Ala167Thr)	PARS2	Uncertain significance	criteria provided, single submitter
632567	NM_152268.4(PARS2):c.239T>C (p.Ile80Thr)	PARS2	Uncertain significance	criteria provided, single submitter
632568	NM_152268.4(PARS2):c.607G>A (p.Glu203Lys)	PARS2	Uncertain significance	criteria provided, single submitter
632570	NM_152268.4(PARS2):c.604C>G (p.Arg202Gly)	PARS2	Uncertain significance	criteria provided, single submitter
982976	NM_152268.4(PARS2):c.1129C>T (p.Pro377Ser)	PARS2	Uncertain significance	criteria provided, single submitter
983148	NM_152268.4(PARS2):c.340G>A (p.Gly114Ser)	PARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PARS2	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 75	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PARS2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PARS2	HGNC:30563	ENSG00000162396	Q7L3T8	Probable proline–tRNA ligase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PARS2	Probable proline–tRNA ligase, mitochondrial	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PARS2	Other/Unknown	no		aa-tRNA-synt_IIb, Pro-tRNA-ligase_IIa, Anticodon-bd

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
primordial germ cell in gonad	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PARS2	193	ubiquitous	yes	secondary oocyte, oocyte, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PARS2	2,295

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PARS2	Q7L3T8	88.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial tRNA aminoacylation	1	519.1×	0.007	PARS2
tRNA Aminoacylation	1	285.5×	0.007	PARS2
Translation	1	62.1×	0.021	PARS2
Metabolism of proteins	1	12.4×	0.081	PARS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
prolyl-tRNA aminoacylation	1	8426.0×	1e-04	PARS2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PARS2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.