Myopathy, lactic acidosis, and sideroblastic anemia 2

Summary

Myopathy, lactic acidosis, and sideroblastic anemia 2 (MONDO:0013307) is a disease caused by YARS2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: YARS2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 60

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, lactic acidosis, and sideroblastic anemia 2
Mondo ID	MONDO:0013307
OMIM	613561
DOID	DOID:0111186
UMLS	C3150802
MedGen	462152
GARD	0015676
Is cancer (heuristic)	no

Also known as: mitochondrial myopathy and sideroblastic anaemia caused by mutation in YARS2 · mitochondrial myopathy and sideroblastic anemia caused by mutation in YARS2 · MLASA2 · myopathy, lactic acidosis, and sideroblastic Anaemia type 2 · myopathy, lactic acidosis, and sideroblastic anemia 2 · myopathy, lactic acidosis, and sideroblastic Anemia type 2 · YARS2 mitochondrial myopathy and sideroblastic anaemia · YARS2 mitochondrial myopathy and sideroblastic anemia

Data availability: 60 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › myopathy, lactic acidosis, and sideroblastic anemia › myopathy, lactic acidosis, and sideroblastic anemia 2

Related subtypes (2): myopathy, lactic acidosis, and sideroblastic anemia 3, myopathy, lactic acidosis, and sideroblastic anemia 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

60 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 13 conflicting classifications of pathogenicity, 12 benign/likely benign, 5 pathogenic, 4 pathogenic/likely pathogenic, 2 benign, 2 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
102433	NM_001040436.3(YARS2):c.137G>A (p.Gly46Asp)	YARS2	Pathogenic	criteria provided, single submitter
102434	NM_001040436.3(YARS2):c.572G>A (p.Gly191Asp)	YARS2	Pathogenic	no assertion criteria provided
102435	NM_001040436.3(YARS2):c.1078C>T (p.Arg360Ter)	YARS2	Pathogenic	no assertion criteria provided
102436	NM_001040436.3(YARS2):c.1303A>G (p.Ser435Gly)	YARS2	Pathogenic	no assertion criteria provided
1056	NM_001040436.3(YARS2):c.156C>G (p.Phe52Leu)	YARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209208	NM_001040436.3(YARS2):c.359dup (p.Asp121fs)	YARS2	Pathogenic	criteria provided, single submitter
215421	NM_001040436.3(YARS2):c.933C>G (p.Asp311Glu)	YARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2159512	NM_001040436.3(YARS2):c.98C>A (p.Ser33Ter)	YARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776783	NM_001040436.3(YARS2):c.948_957del	YARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209209	NM_001040436.3(YARS2):c.751A>G (p.Ile251Val)	YARS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
215418	NM_001040436.3(YARS2):c.202G>A (p.Gly68Ser)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215425	NM_001040436.3(YARS2):c.1275-2dup	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308454	NM_001040436.3(YARS2):c.934G>C (p.Asp312His)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308455	NM_001040436.3(YARS2):c.930G>A (p.Pro310=)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308458	NM_001040436.3(YARS2):c.819A>G (p.Leu273=)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308459	NM_001040436.3(YARS2):c.626A>G (p.Lys209Arg)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308461	NM_001040436.3(YARS2):c.535A>C (p.Lys179Gln)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308462	NM_001040436.3(YARS2):c.477C>T (p.Phe159=)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308464	NM_001040436.3(YARS2):c.234T>C (p.Cys78=)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308465	NM_001040436.3(YARS2):c.180G>A (p.Glu60=)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308466	NM_001040436.3(YARS2):c.30C>T (p.Ser10=)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
594785	NM_001040436.3(YARS2):c.634G>T (p.Glu212Ter)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
725129	NM_001040436.3(YARS2):c.810C>T (p.Thr270=)	YARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028984	NM_001040436.3(YARS2):c.1427A>G (p.Gln476Arg)	YARS2	Uncertain significance	criteria provided, single submitter
1678585	NM_001040436.3(YARS2):c.7G>A (p.Ala3Thr)	YARS2	Uncertain significance	criteria provided, single submitter
2690456	NM_001040436.3(YARS2):c.1241G>T (p.Arg414Leu)	YARS2	Uncertain significance	criteria provided, single submitter
308440	NM_001040436.3(YARS2):c.*627A>T	YARS2	Uncertain significance	criteria provided, single submitter
308442	NM_001040436.3(YARS2):c.*360A>G	YARS2	Uncertain significance	criteria provided, single submitter
308447	NM_001040436.3(YARS2):c.*142T>C	YARS2	Uncertain significance	criteria provided, single submitter
308449	NM_001040436.3(YARS2):c.*62G>A	YARS2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
YARS2	Definitive	Autosomal recessive	myopathy, lactic acidosis, and sideroblastic anemia 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
YARS2	Orphanet:2598	Mitochondrial myopathy and sideroblastic anemia

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
YARS2	HGNC:24249	ENSG00000139131	Q9Y2Z4	Tyrosine–tRNA ligase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
YARS2	Tyrosine–tRNA ligase, mitochondrial	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).

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)
YARS2	Enzyme (other)	yes	6.1.1.1	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ic, Tyr-tRNA-ligase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
YARS2	276	ubiquitous	marker	oocyte, secondary oocyte, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
YARS2	3,284

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
YARS2	Q9Y2Z4	2

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	YARS2
tRNA Aminoacylation	1	285.5×	0.007	YARS2
Translation	1	62.1×	0.021	YARS2
Metabolism of proteins	1	12.4×	0.081	YARS2

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 tyrosyl-tRNA aminoacylation	1	16852.0×	2e-04	YARS2
tRNA aminoacylation	1	8426.0×	2e-04	YARS2
translation	1	102.8×	0.010	YARS2

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
YARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
YARS2	6.1.1.1	tyrosine-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	YARS2
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)
YARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.