Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2

Summary

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2 (MONDO:0030375) is a disease caused by YARS1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: YARS1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2
Mondo ID	MONDO:0030375
OMIM	619418
UMLS	C5543623
MedGen	1778117
GARD	0027928
Is cancer (heuristic)	no

Also known as: IMNEPD2

Data availability: 20 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset › neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2

Related subtypes (1): neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1

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:

9 uncertain significance, 4 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
68154	NM_000487.6(ARSA):c.883G>A (p.Gly295Ser)	ARSA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
996695	NM_003680.4(YARS1):c.806T>C (p.Phe269Ser)	LOC126805688	Pathogenic/Likely pathogenic	no assertion criteria provided
446531	NM_003680.4(YARS1):c.638C>T (p.Pro213Leu)	YARS1	Pathogenic	no assertion criteria provided
446532	NM_003680.4(YARS1):c.1573G>A (p.Gly525Arg)	YARS1	Pathogenic	no assertion criteria provided
6189	NM_003680.4(YARS1):c.586G>A (p.Glu196Lys)	YARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
662296	NM_003680.4(YARS1):c.499C>A (p.Pro167Thr)	YARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292337	NM_003680.4(YARS1):c.499C>G (p.Pro167Ala)	YARS1	Likely pathogenic	criteria provided, single submitter
297155	NM_003680.4(YARS1):c.874T>G (p.Tyr292Asp)	LOC126805688	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297154	NM_003680.4(YARS1):c.946G>A (p.Ala316Thr)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
567612	NM_003680.4(YARS1):c.1099C>T (p.Arg367Trp)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
576327	NM_003680.4(YARS1):c.176T>C (p.Ile59Thr)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3252054	NM_003680.4(YARS1):c.689C>T (p.Ser230Phe)	LOC126805688	Uncertain significance	criteria provided, multiple submitters, no conflicts
4292451	NM_003680.4(YARS1):c.790A>T (p.Ile264Phe)	LOC126805688	Uncertain significance	criteria provided, single submitter
2076158	NM_003680.4(YARS1):c.1435GAG[1] (p.Glu480del)	YARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2139189	NM_003680.4(YARS1):c.1078C>G (p.Pro360Ala)	YARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2692307	NM_003680.4(YARS1):c.640A>G (p.Met214Val)	YARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3391353	NM_003680.4(YARS1):c.591+6T>A	YARS1	Uncertain significance	criteria provided, single submitter
574877	NM_003680.4(YARS1):c.181G>A (p.Asp61Asn)	YARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
942051	NM_003680.4(YARS1):c.322A>G (p.Ile108Val)	YARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
986742	NM_003680.4(YARS1):c.611A>C (p.Tyr204Ser)	YARS1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
YARS1	Strong	Autosomal recessive	neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
YARS1	Orphanet:100045	Autosomal dominant intermediate Charcot-Marie-Tooth disease type C
ARSA	Orphanet:309256	Metachromatic leukodystrophy, late infantile form
ARSA	Orphanet:309263	Metachromatic leukodystrophy, juvenile form
ARSA	Orphanet:309271	Metachromatic leukodystrophy, adult form

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
YARS1	HGNC:12840	ENSG00000134684	P54577	Tyrosine–tRNA ligase, cytoplasmic	gencc,clinvar
ARSA	HGNC:713	ENSG00000100299	P15289	Arylsulfatase A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
YARS1	Tyrosine–tRNA ligase, cytoplasmic	Tyrosine–tRNA ligase that catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).
ARSA	Arylsulfatase A	Hydrolyzes cerebroside sulfate.

Protein-family classification

Druggable: 2 · 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
Phosphatase	1	42.0×	0.047
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
YARS1	Enzyme (other)	yes	6.1.1.1	aa-tRNA-synth_Ic, Tyr-tRNA-ligase, tRNA-bd_dom
ARSA	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
left adrenal gland	1
right adrenal gland	1
granulocyte	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
YARS1	290	ubiquitous	marker	islet of Langerhans, right adrenal gland, left adrenal gland
ARSA	177	ubiquitous	marker	right uterine tube, right testis, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
YARS1	4,793
ARSA	1,356

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARSA	P15289	10
YARS1	P54577	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
The activation of arylsulfatases	1	439.2×	0.015	ARSA
Cytosolic tRNA aminoacylation	1	219.6×	0.015	YARS1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	211.5×	0.015	ARSA
Glycosphingolipid metabolism	1	150.3×	0.015	ARSA
Glycosphingolipid catabolism	1	146.4×	0.015	ARSA
tRNA Aminoacylation	1	142.8×	0.015	YARS1
Metabolism of proteins	2	12.4×	0.015	YARS1, ARSA
Sphingolipid metabolism	1	84.0×	0.022	ARSA
Translation	1	31.0×	0.053	YARS1
Metabolism of lipids	1	15.8×	0.094	ARSA
Innate Immune System	1	12.8×	0.105	ARSA
Neutrophil degranulation	1	11.5×	0.106	ARSA
Post-translational protein modification	1	9.6×	0.117	ARSA
Immune System	1	6.5×	0.159	ARSA
Metabolism	1	5.8×	0.165	ARSA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tyrosyl-tRNA aminoacylation	1	8426.0×	5e-04	YARS1
response to starvation	1	234.1×	0.009	YARS1
lipid metabolic process	1	45.8×	0.029	ARSA
apoptotic process	1	14.3×	0.068	YARS1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
YARS1	CAPSAICIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
YARS1	2	4
ARSA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPSAICIN	4	YARS1
CRENOLANIB	3	YARS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
YARS1	16	Binding:16
ARSA	4	Binding:3, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
YARS1	6.1.1.1	tyrosine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
CAPSAICIN	4	YARS1
CRENOLANIB	3	YARS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	YARS1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ARSA
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)
ARSA	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.