Leukoencephalopathy, progressive, with ovarian failure

Summary

Leukoencephalopathy, progressive, with ovarian failure (MONDO:0014387) is a disease caused by AARS2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: AARS2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 41

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy, progressive, with ovarian failure
Mondo ID	MONDO:0014387
OMIM	615889
DOID	DOID:0070396
UMLS	C4014588
MedGen	863025
GARD	0018252
Is cancer (heuristic)	no

Also known as: leukoencephalopathy, progressive, with ovarian failure · LKENP

Data availability: 41 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › leukoencephalopathy with vanishing white matter › leukoencephalopathy, progressive, with ovarian failure

Related subtypes (8): congenital or early infantile CACH syndrome, late infantile CACH syndrome, juvenile or adult CACH syndrome, leukoencephalopathy with vanishing white matter 1, leukoencephalopathy with vanishing white matter 2, leukoencephalopathy with vanishing white matter 3, leukoencephalopathy with vanishing white matter 4, leukoencephalopathy with vanishing white matter 5

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

41 retrieved; paginated sample, class counts are floors:

10 likely pathogenic, 9 benign, 7 uncertain significance, 6 pathogenic, 5 pathogenic/likely pathogenic, 3 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322076	NM_020745.4(AARS2):c.387CTT[1] (p.Phe131del)	AARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143045	NM_020745.4(AARS2):c.149T>G (p.Phe50Cys)	AARS2	Pathogenic	no assertion criteria provided
143046	NM_020745.4(AARS2):c.1561C>T (p.Arg521Ter)	AARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1699307	NM_020745.4(AARS2):c.87_88dup (p.Leu30fs)	AARS2	Pathogenic	criteria provided, single submitter
213963	NM_020745.4(AARS2):c.595C>T (p.Arg199Cys)	AARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2576588	NM_020745.4(AARS2):c.2611dup (p.Thr871fs)	AARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
30940	NM_020745.4(AARS2):c.1774C>T (p.Arg592Trp)	AARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779313	NM_020745.4(AARS2):c.1940del (p.Gly647fs)	AARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545896	NM_020745.4(AARS2):c.781del (p.Gln261fs)	AARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632487	NM_020745.4(AARS2):c.1040+1G>A	AARS2	Pathogenic	criteria provided, single submitter
982774	NM_020745.4(AARS2):c.1871G>A (p.Trp624Ter)	AARS2	Pathogenic	criteria provided, single submitter
1027410	NM_020745.4(AARS2):c.446G>A (p.Cys149Tyr)	AARS2	Likely pathogenic	criteria provided, single submitter
1027411	NM_020745.4(AARS2):c.385A>C (p.Thr129Pro)	AARS2	Likely pathogenic	criteria provided, single submitter
1707535	NM_020745.4(AARS2):c.1695C>G (p.Tyr565Ter)	AARS2	Likely pathogenic	criteria provided, single submitter
2385967	NM_020745.4(AARS2):c.2872C>T (p.Arg958Ter)	AARS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2575889	NM_020745.4(AARS2):c.2255+5G>A	AARS2	Likely pathogenic	criteria provided, single submitter
2575890	NM_020745.4(AARS2):c.804G>A (p.Met268Ile)	AARS2	Likely pathogenic	criteria provided, single submitter
2585003	NM_020745.4(AARS2):c.2476C>T (p.Arg826Ter)	AARS2	Likely pathogenic	criteria provided, single submitter
3767182	NM_020745.3:c.(759+1_760-1)_(1198+1_1199-1)del	AARS2	Likely pathogenic	criteria provided, single submitter
3775966	NM_020745.4(AARS2):c.521del (p.Gly174fs)	AARS2	Likely pathogenic	criteria provided, single submitter
4292427	NM_020745.4(AARS2):c.584_585del (p.Val195fs)	AARS2	Likely pathogenic	criteria provided, single submitter
213952	NM_020745.4(AARS2):c.31_39del (p.Leu12_Arg14del)	AARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030725	NM_020745.4(AARS2):c.1157C>T (p.Ala386Val)	AARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
143047	NM_020745.4(AARS2):c.2893G>A (p.Gly965Arg)	AARS2	Uncertain significance	criteria provided, single submitter
143048	NM_020745.4(AARS2):c.1213G>A (p.Glu405Lys)	AARS2	Uncertain significance	criteria provided, single submitter
1699302	NM_020745.4(AARS2):c.1687A>T (p.Asn563Tyr)	AARS2	Uncertain significance	criteria provided, single submitter
1708963	NM_020745.4(AARS2):c.907C>A (p.Pro303Thr)	AARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585008	NM_020745.4(AARS2):c.995G>A (p.Ser332Asn)	AARS2	Uncertain significance	criteria provided, single submitter
812989	NM_020745.4(AARS2):c.302G>A (p.Arg101His)	AARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1164206	NM_020745.4(AARS2):c.1015A>G (p.Ile339Val)	AARS2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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
AARS2	Definitive	Autosomal recessive	leukoencephalopathy, progressive, with ovarian failure	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AARS2	Orphanet:313808	Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
AARS2	Orphanet:319504	Combined oxidative phosphorylation defect type 8
AARS2	Orphanet:99853	Ovarioleukodystrophy

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
AARS2	HGNC:21022	ENSG00000124608	Q5JTZ9	Alanine–tRNA ligase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AARS2	Alanine–tRNA ligase, mitochondrial	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AARS2	Enzyme (other)	yes	6.1.1.7	Ala-tRNA-lgiase_IIc, Transl_B-barrel_sf, tRNA_SAD

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
cardiac muscle of right atrium	1
left ventricle myocardium	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AARS2	246	ubiquitous	yes	cardiac muscle of right atrium, tendon of biceps brachii, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AARS2	3,695

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AARS2	Q5JTZ9	3

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	AARS2
tRNA Aminoacylation	1	285.5×	0.007	AARS2
Translation	1	62.1×	0.021	AARS2
Metabolism of proteins	1	12.4×	0.081	AARS2

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
mitochondrial alanyl-tRNA aminoacylation	1	16852.0×	1e-04	AARS2
negative regulation of cGAS/STING signaling pathway	1	1053.2×	9e-04	AARS2

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
AARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AARS2	6.1.1.7	alanine-tRNA ligase

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	1	AARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
AARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.