Pontocerebellar hypoplasia type 1

Summary

Pontocerebellar hypoplasia type 1 (MONDO:0016396) is a disease with 6 cohort genes. The dominant Reactome pathway is mRNA decay by 3’ to 5’ exoribonuclease (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 6
• ClinVar variants: 33
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001265	Hyporeflexia	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002398	Degeneration of anterior horn cells	Very frequent (80-99%)
HP:0002878	Respiratory failure	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Very frequent (80-99%)
HP:0000253	Progressive microcephaly	Frequent (30-79%)
HP:0000529	Progressive visual loss	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012110	Hypoplasia of the pons	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001308	Tongue fasciculations	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002350	Cerebellar cyst	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0004886	Congenital laryngeal stridor	Occasional (5-29%)
HP:0033725	Thin corpus callosum	Occasional (5-29%)
HP:0000565	Esotropia	Very rare (<1-4%)
HP:0001251	Ataxia	Very rare (<1-4%)
HP:0002804	Arthrogryposis multiplex congenita	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 1
Mondo ID	MONDO:0016396
MeSH	C548069
Orphanet	2254
DOID	DOID:0112322
ICD-11	1227773923
SNOMED CT	718610008
UMLS	C5442006
MedGen	1780208
GARD	0010704
Is cancer (heuristic)	no

Also known as: mental retardation, autosomal recessive 32 · MRT32 · Norman disease · PCH1

Data availability: 33 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › pontocerebellar hypoplasia type 1

Related subtypes (56): Neu-Laxova syndrome, inborn mitochondrial metabolism disorder, Ehlers-Danlos syndrome, spondylodysplastic type, MGAT2-congenital disorder of glycosylation, ALDH18A1-related de Barsy syndrome, classic homocystinuria, Larsen-like syndrome, B3GAT3 type, Nijmegen breakage syndrome, Peters plus syndrome, Wiedemann-Rautenstrauch syndrome, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, SHORT syndrome, mucosulfatidosis, CHIME syndrome, creatine transporter deficiency, multiple congenital anomalies-hypotonia-seizures syndrome 2, SLC35A2-congenital disorder of glycosylation, SSR4-congenital disorder of glycosylation, Fabry disease, occipital horn syndrome, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, B4GALT1-congenital disorder of glycosylation, AICA-ribosiduria, COG7-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, Al-Gazali syndrome, COG1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, Nijmegen breakage syndrome-like disorder, multiple congenital anomalies-hypotonia-seizures syndrome 1, multiple congenital anomalies-hypotonia-seizures syndrome 3, autism spectrum disorder - epilepsy - arthrogryposis syndrome, cutis laxa, autosomal dominant 3, SLC39A8-CDG, transketolase deficiency, mucopolysaccharidosis-plus syndrome, Cockayne syndrome, mandibuloacral dysplasia, hyperphosphatasia-intellectual disability syndrome, arthrogryposis-renal dysfunction-cholestasis syndrome, CADDS, XYLT1-congenital disorder of glycosylation, hypophosphatasia, sterol biosynthesis disorder, mucolipidosis, mucopolysaccharidosis, oligosaccharidosis, encephalopathy due to sulfite oxidase deficiency, Fanconi anemia, autosomal recessive cutis laxa type 2, Zellweger spectrum disorders, pseudohypoparathyroidism, developmental and epileptic encephalopathy, 77, glycosylphosphatidylinositol biosynthesis defect 15, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN

Subtypes (3): pontocerebellar hypoplasia type 1A, pontocerebellar hypoplasia type 1B, pontocerebellar hypoplasia, type 1C

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:

18 uncertain significance, 4 pathogenic, 3 conflicting classifications of pathogenicity, 3 likely benign, 2 benign, 2 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
31688	NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)	EXOSC3	Pathogenic	criteria provided, multiple submitters, no conflicts
584083	NC_000014.9:g.(?96846075)(96847364_?)del	VRK1	Pathogenic	criteria provided, single submitter
643149	NC_000014.9:g.(?96856120)(96860745_?)del	VRK1	Pathogenic	criteria provided, single submitter
657389	NC_000014.9:g.(?96810669)(96860745_?)del	VRK1	Pathogenic	criteria provided, single submitter
567048	NM_003384.2(VRK1):c.318_889+1945del	VRK1	Likely pathogenic	criteria provided, single submitter
842535	NM_003384.3(VRK1):c.402_890-895del	VRK1	Likely pathogenic	criteria provided, single submitter
130730	NM_003384.3(VRK1):c.858G>T (p.Met286Ile)	VRK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286548	NM_003384.3(VRK1):c.882C>G (p.Asn294Lys)	VRK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315124	NM_003384.3(VRK1):c.1069-9A>G	VRK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212586	NM_003384.3(VRK1):c.1150A>G (p.Ile384Val)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
315123	NM_003384.3(VRK1):c.901A>G (p.Lys301Glu)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
449197	NM_003384.3(VRK1):c.526G>A (p.Gly176Arg)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
451762	NM_003384.3(VRK1):c.1021C>T (p.Leu341Phe)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
464941	NM_003384.3(VRK1):c.704G>A (p.Gly235Asp)	VRK1	Uncertain significance	criteria provided, single submitter
574450	NM_003384.3(VRK1):c.7_8delinsTT (p.Arg3Phe)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
575292	NM_003384.3(VRK1):c.307C>T (p.Arg103Cys)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
577380	NM_003384.3(VRK1):c.1180G>A (p.Val394Ile)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
641662	NM_003384.3(VRK1):c.161-3C>T	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
647253	NM_003384.3(VRK1):c.1070A>T (p.Lys357Met)	VRK1	Uncertain significance	criteria provided, single submitter
664847	NM_003384.3(VRK1):c.701A>G (p.Asn234Ser)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
664857	NM_003384.3(VRK1):c.308G>A (p.Arg103His)	VRK1	Uncertain significance	criteria provided, single submitter
956220	NM_003384.3(VRK1):c.494T>C (p.Leu165Pro)	VRK1	Uncertain significance	criteria provided, single submitter
990857	NM_003384.3(VRK1):c.29G>A (p.Gly10Glu)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
990858	NM_003384.3(VRK1):c.830G>A (p.Arg277Lys)	VRK1	Uncertain significance	criteria provided, single submitter
990860	NM_003384.3(VRK1):c.841A>G (p.Asn281Asp)	VRK1	Uncertain significance	no assertion criteria provided
990861	NM_003384.3(VRK1):c.1064C>G (p.Thr355Arg)	VRK1	Uncertain significance	no assertion criteria provided
990862	NM_003384.3(VRK1):c.1142A>G (p.Glu381Gly)	VRK1	Uncertain significance	no assertion criteria provided
130732	NM_003384.3(VRK1):c.705C>T (p.Gly235=)	VRK1	Benign	criteria provided, multiple submitters, no conflicts
315122	NM_003384.3(VRK1):c.375-8G>C	VRK1	Benign	criteria provided, multiple submitters, no conflicts
702227	NM_003384.3(VRK1):c.576+8T>C	VRK1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 37 · Orphanet: 8 · 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
EXOSC3	Definitive	Autosomal recessive	pontocerebellar hypoplasia type 1B	6
EXOSC8	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 1C	5
EXOSC9	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 1D	5
SLC25A46	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 1E	8
VRK1	Strong	Autosomal recessive	pontocerebellar hypoplasia type 1A	8
AGTPBP1	Supportive	Autosomal recessive	pontocerebellar hypoplasia type 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VRK1	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:423894	Microcephaly-complex motor and sensory axonal neuropathy syndrome
EXOSC3	Orphanet:2254	Pontocerebellar hypoplasia type 1
EXOSC8	Orphanet:2254	Pontocerebellar hypoplasia type 1
AGTPBP1	Orphanet:2254	Pontocerebellar hypoplasia type 1
SLC25A46	Orphanet:2254	Pontocerebellar hypoplasia type 1
SLC25A46	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
EXOSC9	Orphanet:2254	Pontocerebellar hypoplasia type 1

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	gencc,clinvar
EXOSC3	HGNC:17944	ENSG00000107371	Q9NQT5	Exosome complex component RRP40	gencc,clinvar
EXOSC8	HGNC:17035	ENSG00000120699	Q96B26	Exosome complex component RRP43	gencc
AGTPBP1	HGNC:17258	ENSG00000135049	Q9UPW5	Cytosolic carboxypeptidase 1	gencc
SLC25A46	HGNC:25198	ENSG00000164209	Q96AG3	Mitochondrial outer membrane protein SLC25A46	gencc
EXOSC9	HGNC:9137	ENSG00000123737	Q06265	Exosome complex component RRP45	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VRK1	Serine/threonine-protein kinase VRK1	Serine/threonine kinase involved in the regulation of key cellular processes including the cell cycle, nuclear condensation, transcription regulation, and DNA damage response.
EXOSC3	Exosome complex component RRP40	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.
EXOSC8	Exosome complex component RRP43	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.
AGTPBP1	Cytosolic carboxypeptidase 1	Metallocarboxypeptidase that mediates protein deglutamylation of tubulin and non-tubulin target proteins.
SLC25A46	Mitochondrial outer membrane protein SLC25A46	Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization.
EXOSC9	Exosome complex component RRP45	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.33

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
Scaffold/PPI	2	5.8×	0.172
Protease	1	6.1×	0.264
Kinase	1	4.6×	0.264
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VRK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
EXOSC3	Other/Unknown	no		KH_dom_type_1, NA-bd_OB-fold, Exosome_RNA_bind1/RRP40/RRP4
EXOSC8	Scaffold/PPI	no		ExoRNase_PH_dom1, ExoRNase_PH_dom2, Ribosomal_Su5_D2-typ_SF
AGTPBP1	Protease	yes	3.4.17.24	Peptidase_M14, ARM-like, ARM-type_fold
SLC25A46	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, SLC25A46
EXOSC9	Scaffold/PPI	no		ExoRNase_PH_dom1, ExoRNase_PH_dom2, Ribosomal_Su5_D2-typ_SF

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	4
secondary oocyte	4
bone marrow	1
tendon of biceps brachii	1
ganglionic eminence	1
right uterine tube	1
ventricular zone	1
corpus callosum	1
cortical plate	1
monocyte	1
sperm	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte
EXOSC3	246	ubiquitous	marker	oocyte, secondary oocyte, tendon of biceps brachii
EXOSC8	298	ubiquitous	marker	ventricular zone, ganglionic eminence, right uterine tube
AGTPBP1	280	ubiquitous	marker	cortical plate, corpus callosum, monocyte
SLC25A46	290	ubiquitous	marker	sperm, secondary oocyte, oocyte
EXOSC9	285	ubiquitous	marker	secondary oocyte, oocyte, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VRK1	3,022
EXOSC8	2,862
EXOSC9	2,532
EXOSC3	2,330
SLC25A46	1,557
AGTPBP1	815

Intra-cohort edges

A	B	Sources
EXOSC3	EXOSC8	biogrid_interaction, intact, string_interaction
EXOSC3	EXOSC9	biogrid_interaction, intact, string_interaction
EXOSC3	VRK1	string_interaction
EXOSC8	EXOSC9	biogrid_interaction, intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VRK1	Q99986	26
EXOSC3	Q9NQT5	8
EXOSC8	Q96B26	8
EXOSC9	Q06265	8
SLC25A46	Q96AG3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGTPBP1	Q9UPW5	75.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
mRNA decay by 3’ to 5’ exoribonuclease	3	428.2×	1e-07	EXOSC3, EXOSC8, EXOSC9
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	3	380.7×	1e-07	EXOSC3, EXOSC8, EXOSC9
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	3	380.7×	1e-07	EXOSC3, EXOSC8, EXOSC9
KSRP (KHSRP) binds and destabilizes mRNA	3	380.7×	1e-07	EXOSC3, EXOSC8, EXOSC9
ATF4 activates genes in response to endoplasmic reticulum stress	3	244.7×	3e-07	EXOSC3, EXOSC8, EXOSC9
Nuclear RNA decay	3	185.2×	6e-07	EXOSC3, EXOSC8, EXOSC9
Major pathway of rRNA processing in the nucleolus and cytosol	3	37.0×	7e-05	EXOSC3, EXOSC8, EXOSC9
Initiation of Nuclear Envelope (NE) Reformation	1	120.2×	0.012	VRK1
Nuclear Envelope Breakdown	1	91.4×	0.015	VRK1
Carboxyterminal post-translational modifications of tubulin	1	47.6×	0.025	AGTPBP1
Post-translational protein modification	1	3.8×	0.256	AGTPBP1
Metabolism of proteins	1	2.5×	0.344	AGTPBP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
exonucleolytic trimming to generate mature 3’-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	3	1203.7×	2e-08	EXOSC3, EXOSC8, EXOSC9
nuclear polyadenylation-dependent rRNA catabolic process	3	1203.7×	2e-08	EXOSC3, EXOSC8, EXOSC9
TRAMP-dependent tRNA surveillance pathway	3	1203.7×	2e-08	EXOSC3, EXOSC8, EXOSC9
U4 snRNA 3’-end processing	3	1053.2×	2e-08	EXOSC3, EXOSC8, EXOSC9
RNA catabolic process	3	227.7×	2e-06	EXOSC3, EXOSC8, EXOSC9
U1 snRNA 3’-end processing	2	1872.4×	3e-06	EXOSC8, EXOSC9
U5 snRNA 3’-end processing	2	1872.4×	3e-06	EXOSC8, EXOSC9
RNA processing	3	109.4×	1e-05	EXOSC3, EXOSC8, EXOSC9
nuclear mRNA surveillance	2	624.1×	3e-05	EXOSC8, EXOSC9
cerebellar Purkinje cell differentiation	2	351.1×	8e-05	AGTPBP1, SLC25A46
rRNA catabolic process	2	330.4×	8e-05	EXOSC8, EXOSC9
nuclear-transcribed mRNA catabolic process	2	255.3×	1e-04	EXOSC3, EXOSC9
mRNA catabolic process	2	165.2×	3e-04	EXOSC3, EXOSC9
mitochondrial membrane fission	1	1404.3×	0.003	SLC25A46
anterograde axonal transport of mitochondrion	1	1404.3×	0.003	AGTPBP1
rRNA processing	2	47.2×	0.003	EXOSC3, EXOSC9
protein deglutamylation	1	936.2×	0.004	AGTPBP1
retrograde axonal transport of mitochondrion	1	936.2×	0.004	AGTPBP1
positive regulation of protein localization to chromatin	1	936.2×	0.004	VRK1
eye photoreceptor cell differentiation	1	702.2×	0.004	AGTPBP1
Cajal body organization	1	702.2×	0.004	VRK1
C-terminal protein deglutamylation	1	702.2×	0.004	AGTPBP1
DNA deamination	1	702.2×	0.004	EXOSC3
peripheral nervous system neuron axonogenesis	1	702.2×	0.004	SLC25A46
CUT catabolic process	1	702.2×	0.004	EXOSC3
protein side chain deglutamylation	1	468.1×	0.005	AGTPBP1
Golgi disassembly	1	468.1×	0.005	VRK1
respiratory chain complex IV assembly	1	401.2×	0.005	SLC25A46
locomotion involved in locomotory behavior	1	401.2×	0.005	SLC25A46
poly(A)-dependent snoRNA 3’-end processing	1	351.1×	0.006	EXOSC3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EXOSC9	1	2
VRK1	0	0
EXOSC3	0	0
EXOSC8	0	0
AGTPBP1	0	0
SLC25A46	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	EXOSC9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VRK1	74	Binding:74
EXOSC9	7	Binding:7
AGTPBP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGTPBP1	3.4.17.24	tubulin-glutamate carboxypeptidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	EXOSC9

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	1	EXOSC9
C	Druggable family + PDB, no drug	1	VRK1
D	Druggable family + AlphaFold only, no drug	1	AGTPBP1
E	Difficult family or no structure, no drug	3	EXOSC3, EXOSC8, SLC25A46

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
EXOSC3	0	EXOSC9
VRK1	74	—
EXOSC8	0	—
AGTPBP1	1	—
SLC25A46	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.