Perrault syndrome 2
diseaseOn this page
Also known as HARS2 Perrault syndromePerrault syndrome caused by mutation in HARS2Perrault syndrome type 2PRLTS2
Summary
Perrault syndrome 2 (MONDO:0013972) is a disease caused by HARS2 (GenCC Strong), with 1 cohort gene.
At a glance
- Causal gene: HARS2 (GenCC Strong)
- Cohort genes: 1
- ClinVar variants: 33
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Perrault syndrome 2 |
| Mondo ID | MONDO:0013972 |
| OMIM | 614926 |
| Orphanet | 642976 |
| DOID | DOID:0061117 |
| UMLS | C3554105 |
| MedGen | 767019 |
| GARD | 0015882 |
| Is cancer (heuristic) | no |
Also known as: HARS2 Perrault syndrome · Perrault syndrome 2 · Perrault syndrome caused by mutation in HARS2 · Perrault syndrome type 2 · PRLTS2
Data availability: 33 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 › autosomal genetic disease › autosomal recessive disease › Perrault syndrome › Perrault syndrome 2
Related subtypes (6): Perrault syndrome 1, Perrault syndrome 3, Perrault syndrome 4, Perrault syndrome 5, Perrault syndrome 6, Perrault syndrome 7
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
33 retrieved; paginated sample, class counts are floors:
9 likely pathogenic, 8 conflicting classifications of pathogenicity, 8 uncertain significance, 3 pathogenic/likely pathogenic, 2 benign/likely benign, 2 pathogenic, 1 benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1931186 | NM_012208.4(HARS2):c.475C>T (p.Arg159Ter) | HARS2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 208286 | NM_012208.4(HARS2):c.1102G>T (p.Val368Leu) | HARS2 | Pathogenic/Likely pathogenic | no assertion criteria provided |
| 3601168 | NM_012208.4(HARS2):c.1153_1165del (p.Ile385fs) | HARS2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 3601170 | NM_012208.4(HARS2):c.928del (p.Tyr309_Leu310insTer) | HARS2 | Pathogenic | criteria provided, single submitter |
| 982371 | NM_012208.4(HARS2):c.647G>A (p.Arg216Gln) | HARS2 | Pathogenic | no assertion criteria provided |
| 1185123 | NM_012208.4(HARS2):c.399+1G>A | HARS2 | Likely pathogenic | no assertion criteria provided |
| 1185124 | NM_012208.4(HARS2):c.1403G>C (p.Gly468Ala) | HARS2 | Likely pathogenic | criteria provided, single submitter |
| 2446360 | NM_012208.4(HARS2):c.1273C>T (p.Arg425Trp) | HARS2 | Likely pathogenic | criteria provided, single submitter |
| 3242247 | NM_012208.4(HARS2):c.1012G>A (p.Glu338Lys) | HARS2 | Likely pathogenic | criteria provided, single submitter |
| 3601169 | NM_012208.4(HARS2):c.281A>G (p.Asp94Gly) | HARS2 | Likely pathogenic | criteria provided, single submitter |
| 39620 | NM_012208.4(HARS2):c.598C>G (p.Leu200Val) | HARS2 | Likely pathogenic | criteria provided, single submitter |
| 633638 | NM_012208.4(HARS2):c.137T>A (p.Leu46Gln) | HARS2 | Likely pathogenic | no assertion criteria provided |
| 633639 | NM_012208.4(HARS2):c.980G>A (p.Arg327Gln) | HARS2 | Likely pathogenic | no assertion criteria provided |
| 633640 | NM_012208.4(HARS2):c.259C>T (p.Arg87Cys) | HARS2 | Likely pathogenic | no assertion criteria provided |
| 1176814 | NM_012208.4(HARS2):c.125T>G (p.Leu42Ter) | HARS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1350913 | NM_012208.4(HARS2):c.389A>G (p.Tyr130Cys) | HARS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1964960 | NM_012208.4(HARS2):c.728A>C (p.Asp243Ala) | HARS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 214542 | NM_012208.4(HARS2):c.172A>G (p.Lys58Glu) | HARS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 214543 | NM_012208.4(HARS2):c.448C>T (p.Arg150Cys) | HARS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 225386 | NM_012208.4(HARS2):c.489dup (p.Ile164fs) | HARS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 3711639 | NM_012208.4(HARS2):c.634-2A>G | HARS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 635270 | NM_012208.4(HARS2):c.1439G>A (p.Arg480His) | HARS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1185636 | NM_012208.4(HARS2):c.1320G>T (p.Glu440Asp) | HARS2 | Uncertain significance | no assertion criteria provided |
| 1206267 | NM_012208.4(HARS2):c.1254G>C (p.Gln418His) | HARS2 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 1297062 | NM_012208.4(HARS2):c.322T>C (p.Tyr108His) | HARS2 | Uncertain significance | no assertion criteria provided |
| 1805167 | NM_012208.4(HARS2):c.1450_1451delinsC (p.Ser484fs) | HARS2 | Uncertain significance | criteria provided, single submitter |
| 214546 | NM_012208.4(HARS2):c.697C>T (p.Arg233Cys) | HARS2 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 2441989 | NM_012208.4(HARS2):c.1462-3C>T | HARS2 | Uncertain significance | criteria provided, single submitter |
| 3237486 | NM_012208.4(HARS2):c.1039C>G (p.Gln347Glu) | HARS2 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 3893172 | NM_012208.4(HARS2):c.338G>T (p.Gly113Val) | HARS2 | Uncertain significance | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 4 · Orphanet: 2 · 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 |
|---|---|---|---|---|
| HARS2 | Strong | Autosomal recessive | Perrault syndrome 2 | 4 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| HARS2 | Orphanet:642945 | Perrault syndrome type 1 |
| HARS2 | Orphanet:642976 | Perrault syndrome type 2 |
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 |
|---|---|---|---|---|---|
| HARS2 | HGNC:4817 | ENSG00000112855 | P49590 | Histidine–tRNA ligase, mitochondrial | gencc,clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| HARS2 | Histidine–tRNA ligase, mitochondrial | Mitochondrial aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP). |
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) |
|---|---|---|---|---|
| HARS2 | Enzyme (other) | yes | 6.1.1.21 | Anticodon-bd, HisRS/HisZ, aa-tRNA-synth_II |
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 |
|---|---|
| cerebellar cortex | 1 |
| cerebellar hemisphere | 1 |
| right hemisphere of cerebellum | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| HARS2 | 272 | ubiquitous | marker | cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| HARS2 | 2,703 |
Structural data
PDB: 0 · AlphaFold-only: 1 · No structure: 0
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| HARS2 | P49590 | 88.44 |
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 | HARS2 |
| tRNA Aminoacylation | 1 | 285.5× | 0.007 | HARS2 |
| Translation | 1 | 62.1× | 0.021 | HARS2 |
| Metabolism of proteins | 1 | 12.4× | 0.081 | HARS2 |
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 |
|---|---|---|---|---|
| histidyl-tRNA aminoacylation | 1 | 8426.0× | 5e-04 | HARS2 |
| tRNA aminoacylation for protein translation | 1 | 842.6× | 0.002 | HARS2 |
| mitochondrial translation | 1 | 173.7× | 0.008 | HARS2 |
| translation | 1 | 102.8× | 0.010 | HARS2 |
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 |
|---|---|---|
| HARS2 | 0 | 0 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 1.
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| HARS2 | 6.1.1.21 | histidine-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 | 0 | |
| D | Druggable family + AlphaFold only, no drug | 1 | HARS2 |
| 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) |
|---|---|---|
| HARS2 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.
Related Atlas pages
- Cohort genes: HARS2