Pontocerebellar hypoplasia type 6

Summary

Pontocerebellar hypoplasia type 6 (MONDO:0012683) is a disease caused by RARS2 (GenCC Definitive), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include vatiquinone.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RARS2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 324
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 6
Mondo ID	MONDO:0012683
MeSH	C548074
OMIM	611523
Orphanet	166073
DOID	DOID:0060275
ICD-11	1612653027
SNOMED CT	718606005
UMLS	C1969084
MedGen	370596
GARD	0010710
Is cancer (heuristic)	no

Also known as: encephalopathy fatal infantile with mitochondrial respiratory chain defects · fatal infantile encephalopathy with mitochondrial respiratory chain defects · non-syndromic pontocerebellar hypoplasia caused by mutation in RARS2 · PCH6 · pontocerebellar hypoplasia type 6 · pontocerebellar hypoplasia, type 6 · RARS2 non-syndromic pontocerebellar hypoplasia

Data availability: 324 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › pontocerebellar hypoplasia type 6

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

324 retrieved; paginated sample, class counts are floors:

92 likely pathogenic, 73 uncertain significance, 71 pathogenic/likely pathogenic, 41 conflicting classifications of pathogenicity, 15 likely benign, 13 benign, 10 pathogenic, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032075	NM_020320.5(RARS2):c.1554del (p.Arg519fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066551	NM_020320.5(RARS2):c.613-3927C>T	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067780	NM_020320.5(RARS2):c.879-1G>C	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069762	NM_020320.5(RARS2):c.282_285del (p.Arg94fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070705	NM_020320.5(RARS2):c.3G>A (p.Met1Ile)	RARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1074408	NM_020320.5(RARS2):c.284_285del (p.Glu95fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075781	NM_020320.5(RARS2):c.9C>A (p.Cys3Ter)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076286	NM_020320.5(RARS2):c.928dup (p.Ile310fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184397	NM_020320.5(RARS2):c.1312A>T (p.Lys438Ter)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1335989	NM_020320.5(RARS2):c.1246G>T (p.Glu416Ter)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1358974	NM_020320.5(RARS2):c.277_280del (p.Asn93fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362522	NM_020320.5(RARS2):c.716C>G (p.Ser239Ter)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1406532	NM_020320.5(RARS2):c.699_700insACATC (p.Asp234fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1434193	NM_020320.5(RARS2):c.997C>T (p.Arg333Ter)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450145	NM_020320.5(RARS2):c.3G>T (p.Met1Ile)	RARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1451754	NM_020320.5(RARS2):c.622C>T (p.Gln208Ter)	RARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1452675	NM_020320.5(RARS2):c.2T>C (p.Met1Thr)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457359	NM_020320.5(RARS2):c.1A>C (p.Met1Leu)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686119	NM_020320.5(RARS2):c.1390C>T (p.Gln464Ter)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686120	NM_020320.5(RARS2):c.422A>G (p.His141Arg)	RARS2	Pathogenic	criteria provided, single submitter
1927515	NM_020320.5(RARS2):c.1097_1098del (p.Gly365_Tyr366insTer)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1953482	NM_020320.5(RARS2):c.965_966del (p.Tyr322fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1963453	NM_020320.5(RARS2):c.830_831del (p.Gln277fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1970672	NM_020320.5(RARS2):c.1055dup (p.His353fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1994750	NM_020320.5(RARS2):c.1319T>G (p.Leu440Ter)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212016	NM_020320.5(RARS2):c.1054_1055del (p.Lys352fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2127573	NM_020320.5(RARS2):c.1381_1385del (p.Val461fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215055	NM_020320.5(RARS2):c.419T>G (p.Phe140Cys)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215061	NM_020320.5(RARS2):c.943C>T (p.Arg315Ter)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215072	NM_020320.5(RARS2):c.472_474del (p.Lys158del)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
RARS2	Definitive	Autosomal recessive	pontocerebellar hypoplasia type 6	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RARS2	Orphanet:166073	Pontocerebellar hypoplasia type 6
SEPTIN9	Orphanet:2901	Neuralgic amyotrophy

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
RARS2	HGNC:21406	ENSG00000146282	Q5T160	Probable arginine–tRNA ligase, mitochondrial	gencc,clinvar
SEPTIN9	HGNC:7323	ENSG00000184640	Q9UHD8	Septin-9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RARS2	Probable arginine–tRNA ligase, mitochondrial	Catalyzes the attachment of arginine to tRNA(Arg) in a two-step reaction: arginine is first activated by ATP to form Arg-AMP and then transferred to the acceptor end of tRNA(Arg).
SEPTIN9	Septin-9	Filament-forming cytoskeletal GTPase.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RARS2	Other/Unknown	no		Arg-tRNA-ligase, aa-tRNA-synth_I_CS, DALR_anticod-bd
SEPTIN9	Other/Unknown	no		Septin, P-loop_NTPase, G_SEPTIN_dom

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
ileal mucosa	2
adrenal tissue	1
tibialis anterior	1
granulocyte	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RARS2	255	ubiquitous	marker	ileal mucosa, adrenal tissue, tibialis anterior
SEPTIN9	293	ubiquitous	marker	ileal mucosa, granulocyte, thymus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RARS2	2,799
SEPTIN9	2,119

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SEPTIN9	Q9UHD8	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RARS2	Q5T160	89.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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	RARS2
tRNA Aminoacylation	1	285.5×	0.007	RARS2
Translation	1	62.1×	0.021	RARS2
Metabolism of proteins	1	12.4×	0.081	RARS2

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
arginyl-tRNA aminoacylation	1	2808.7×	0.002	RARS2
septin cytoskeleton organization	1	2106.5×	0.002	SEPTIN9
positive regulation of non-motile cilium assembly	1	936.2×	0.003	SEPTIN9
tRNA aminoacylation for protein translation	1	421.3×	0.004	RARS2
cytoskeleton-dependent cytokinesis	1	401.2×	0.004	SEPTIN9
mitochondrial translation	1	86.9×	0.015	RARS2
intracellular protein localization	1	52.3×	0.022	SEPTIN9
actin cytoskeleton organization	1	39.6×	0.025	SEPTIN9

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
SEPTIN9	BARICITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SEPTIN9	3	4
RARS2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BARICITINIB	4	SEPTIN9
TANDUTINIB	2	SEPTIN9
UCN-01	2	SEPTIN9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SEPTIN9	2	Binding:2
RARS2	1	Binding:1

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

3 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)
BARICITINIB	4	SEPTIN9
TANDUTINIB	2	SEPTIN9
UCN-01	2	SEPTIN9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SEPTIN9
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	RARS2

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)
RARS2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VATIQUINONE	3	1