Pontocerebellar hypoplasia

disease

On this page

Also known as isolated pontocerebellar hypoplasianonsyndromic pontocerebellar hypoplasiaPCHpontoneocerebellar atrophypontoneocerebllar hypoplasia

Summary

Pontocerebellar hypoplasia (MONDO:0020135) is a disease (an umbrella term covering 21 Mondo subtypes) with 16 cohort genes. The dominant Reactome pathway is tRNA processing in the nucleus (4 cohort genes).

At a glance

Prevalence: Unknown (Worldwide)
Umbrella term: 21 Mondo subtypes
Cohort genes: 16
ClinVar variants: 262

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia
Mondo ID	MONDO:0020135
MeSH	C580383
OMIM	607596
Orphanet	98523
DOID	DOID:0060264
ICD-11	1565266279
SNOMED CT	45163000
UMLS	C1261175
MedGen	224703
GARD	0010977
NORD	1596
Is cancer (heuristic)	no

Also known as: isolated pontocerebellar hypoplasia · nonsyndromic pontocerebellar hypoplasia · PCH · pontocerebellar hypoplasia · pontoneocerebellar atrophy · pontoneocerebllar hypoplasia

Data availability: 262 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 21 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › pontocerebellar hypoplasia

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

262 retrieved; paginated sample, class counts are floors:

97 uncertain significance, 41 benign, 40 conflicting classifications of pathogenicity, 34 pathogenic/likely pathogenic, 14 likely pathogenic, 14 benign/likely benign, 12 likely benign, 10 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
132810	NM_001368809.2(AMPD2):c.2172G>C (p.Glu724Asp)	AMPD2	Pathogenic	criteria provided, single submitter
132813	NM_001368809.2(AMPD2):c.1859G>A (p.Arg620His)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723362	NM_001368809.2(AMPD2):c.646del (p.Leu216fs)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620339	NM_001368809.2(AMPD2):c.520G>T (p.Glu174Ter)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813899	NM_001368809.2(AMPD2):c.1345C>T (p.Arg449Ter)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143934	NM_006831.3(CLP1):c.419G>A (p.Arg140His)	CLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
129024	NM_016042.4(EXOSC3):c.238G>T (p.Val80Phe)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723242	NM_016042.4(EXOSC3):c.556C>T (p.Arg186Ter)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1878333	NM_016042.4(EXOSC3):c.312_313del (p.Gln105fs)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280004	NM_016042.4(EXOSC3):c.155del (p.Pro52fs)	EXOSC3	Pathogenic	criteria provided, multiple submitters, no conflicts
3366785	NM_016042.4(EXOSC3):c.660dup (p.Val221fs)	EXOSC3	Pathogenic	criteria provided, single submitter
932631	NM_016042.4(EXOSC3):c.2T>C (p.Met1Thr)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549845	NM_005033.3(EXOSC9):c.41T>C (p.Leu14Pro)	EXOSC9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
984624	NM_016955.4(SEPSECS):c.114+3A>G	LOC129992330	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1300179	NM_004897.5(MINPP1):c.1027_1028del (p.Ile343fs)	MINPP1	Pathogenic	criteria provided, single submitter
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
1070705	NM_020320.5(RARS2):c.3G>A (p.Met1Ile)	RARS2	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
215072	NM_020320.5(RARS2):c.472_474del (p.Lys158del)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225026	NM_020320.5(RARS2):c.1A>G (p.Met1Val)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678239	NM_020320.5(RARS2):c.436_437delinsA (p.Arg146fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678252	NM_020320.5(RARS2):c.297+1G>C	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488585	NM_020320.5(RARS2):c.1544A>G (p.Asp515Gly)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
618855	NM_020320.5(RARS2):c.1406G>A (p.Arg469His)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632596	NM_020320.5(RARS2):c.848T>A (p.Leu283Gln)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
872611	NM_020320.5(RARS2):c.2T>G (p.Met1Arg)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
950760	NM_020320.5(RARS2):c.160_161del (p.Asp53_Asn54insTer)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
951758	NM_020320.5(RARS2):c.633_636del (p.Glu212fs)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18401	NM_016955.4(SEPSECS):c.715G>A (p.Ala239Thr)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 18 · 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
ATOH1	Moderate	Autosomal recessive	pontocerebellar hypoplasia	3
HEATR5B	Moderate	Autosomal recessive	pontocerebellar hypoplasia

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
TSEN34	Orphanet:2524	Pontocerebellar hypoplasia type 2
CLP1	Orphanet:411493	Pontocerebellar hypoplasia type 10
EXOSC3	Orphanet:2254	Pontocerebellar hypoplasia type 1
RARS2	Orphanet:166073	Pontocerebellar hypoplasia type 6
VPS53	Orphanet:247198	Progressive cerebello-cerebral atrophy
TSEN54	Orphanet:166063	Pontocerebellar hypoplasia type 4
TSEN54	Orphanet:2524	Pontocerebellar hypoplasia type 2
TSEN2	Orphanet:2524	Pontocerebellar hypoplasia type 2
SEPSECS	Orphanet:247198	Progressive cerebello-cerebral atrophy
SEPSECS	Orphanet:2524	Pontocerebellar hypoplasia type 2
AMPD2	Orphanet:369920	Pontocerebellar hypoplasia type 9
AMPD2	Orphanet:401805	Autosomal recessive spastic paraplegia type 63
MINPP1	Orphanet:284339	Pontocerebellar hypoplasia type 7
MINPP1	Orphanet:319487	Familial papillary or follicular thyroid carcinoma
CHMP1A	Orphanet:324569	Pontocerebellar hypoplasia type 8
EXOSC9	Orphanet:2254	Pontocerebellar hypoplasia type 1

Cohort genes → proteins

16 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	16

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATOH1	HGNC:797	ENSG00000172238	Q92858	Transcription factor ATOH1	gencc,clinvar
HEATR5B	HGNC:29273	ENSG00000008869	Q9P2D3	HEAT repeat-containing protein 5B	gencc
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	clinvar
TSEN34	HGNC:15506	ENSG00000170892	Q9BSV6	tRNA-splicing endonuclease subunit Sen34	clinvar
CLP1	HGNC:16999	ENSG00000172409	Q92989	Polyribonucleotide 5’-hydroxyl-kinase Clp1	clinvar
EXOSC3	HGNC:17944	ENSG00000107371	Q9NQT5	Exosome complex component RRP40	clinvar
RARS2	HGNC:21406	ENSG00000146282	Q5T160	Probable arginine–tRNA ligase, mitochondrial	clinvar
VPS53	HGNC:25608	ENSG00000141252	Q5VIR6	Vacuolar protein sorting-associated protein 53 homolog	clinvar
TBC1D23	HGNC:25622	ENSG00000036054	Q9NUY8	TBC1 domain family member 23	clinvar
TSEN54	HGNC:27561	ENSG00000182173	Q7Z6J9	tRNA-splicing endonuclease subunit Sen54	clinvar
TSEN2	HGNC:28422	ENSG00000154743	Q8NCE0	tRNA-splicing endonuclease subunit Sen2	clinvar
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	clinvar
AMPD2	HGNC:469	ENSG00000116337	Q01433	AMP deaminase 2	clinvar
MINPP1	HGNC:7102	ENSG00000107789	Q9UNW1	Multiple inositol polyphosphate phosphatase 1	clinvar
CHMP1A	HGNC:8740	ENSG00000131165	Q9HD42	Charged multivesicular body protein 1a	clinvar
EXOSC9	HGNC:9137	ENSG00000123737	Q06265	Exosome complex component RRP45	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATOH1	Transcription factor ATOH1	Transcriptional regulator.
HEATR5B	HEAT repeat-containing protein 5B	Component of clathrin-coated vesicles.
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.
TSEN34	tRNA-splicing endonuclease subunit Sen34	Constitutes one of the two catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
CLP1	Polyribonucleotide 5’-hydroxyl-kinase Clp1	Polynucleotide kinase that can phosphorylate the 5’-hydroxyl groups of double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), double-stranded DNA (dsDNA) and double-stranded DNA:RNA hybrids. dsRNA is phosphorylated more efficiently than…
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.
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).
VPS53	Vacuolar protein sorting-associated protein 53 homolog	Acts as a component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN).
TBC1D23	TBC1 domain family member 23	Putative Rab GTPase-activating protein which plays a role in vesicular trafficking.
TSEN54	tRNA-splicing endonuclease subunit Sen54	Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
TSEN2	tRNA-splicing endonuclease subunit Sen2	Constitutes one of the two catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
AMPD2	AMP deaminase 2	AMP deaminase plays a critical role in energy metabolism.
MINPP1	Multiple inositol polyphosphate phosphatase 1	Multiple inositol polyphosphate phosphatase that hydrolyzes 1D-myo-inositol 1,3,4,5,6-pentakisphosphate (InsP5[2OH]) and 1D-myo-inositol hexakisphosphate (InsP6) to a range of less phosphorylated inositol phosphates.
CHMP1A	Charged multivesicular body protein 1a	Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs.
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: 8 · Difficult: 2 · Unknown: 6 · Druggable fraction: 0.5

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)	7	5.2×	8e-04
Kinase	1	1.7×	0.958
Scaffold/PPI	1	1.1×	0.958
Other/Unknown	6	0.7×	0.958
Transcription factor	1	0.5×	0.958

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATOH1	Transcription factor	no		bHLH_dom, ATOH1_bHLH, HLH_DNA-bd_sf
HEATR5B	Other/Unknown	no		ARM-like, ARM-type_fold, Laa1/Sip1/HEATR5
VRK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TSEN34	Enzyme (other)	yes	4.6.1.16	tRNA_splic, tRNA_intron_Endonuc_cat-like, tRNA_endonuc-like_dom_sf
CLP1	Enzyme (other)	yes	2.7.1.78	Clp1_C, P-loop_NTPase, Clp1
EXOSC3	Other/Unknown	no		KH_dom_type_1, NA-bd_OB-fold, Exosome_RNA_bind1/RRP40/RRP4
RARS2	Other/Unknown	no		Arg-tRNA-ligase, aa-tRNA-synth_I_CS, DALR_anticod-bd
VPS53	Other/Unknown	no		Vps53_N, Vps53_C, Vps53_C_sf
TBC1D23	Other/Unknown	no		Rab-GAP-TBC_dom, Rhodanese-like_dom, Rab-GAP_TBC_sf
TSEN54	Enzyme (other)	yes	4.6.1.16	tRNA_splic_suSen54_N, tRNA_splic_suSen54
TSEN2	Enzyme (other)	yes	4.6.1.16	tRNA_splic, tRNA_intron_Endonuc_cat-like, tRNA_intron_Endonuc_N
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
AMPD2	Enzyme (other)	yes	3.5.4.6	AMPD, A/AMP_deam_AS, Metal_Hydrolase
MINPP1	Enzyme (other)	yes	3.1.3.62	His_Pase_clade-2, Histidine_acid_Pase_euk, His_PPase_superfam
CHMP1A	Other/Unknown	no		Snf7_fam
EXOSC9	Scaffold/PPI	no		ExoRNase_PH_dom1, ExoRNase_PH_dom2, Ribosomal_Su5_D2-typ_SF

Expression context

Cohort genes with no expression data: 0.

13 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)	16
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	4
secondary oocyte	4
mucosa of transverse colon	3
ileal mucosa	3
cardiac muscle of right atrium	2
left ventricle myocardium	2
adrenal tissue	2
granulocyte	2
rectum	1
small intestine Peyer’s patch	1
oviduct epithelium	1
bone marrow	1
blood	1
right adrenal gland	1
right adrenal gland cortex	1
epithelium of nasopharynx	1
tendon of biceps brachii	1
tibialis anterior	1
bone marrow cell	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATOH1	26	tissue_specific	marker	mucosa of transverse colon, rectum, small intestine Peyer’s patch
HEATR5B	261	ubiquitous	marker	left ventricle myocardium, oviduct epithelium, cardiac muscle of right atrium
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte
TSEN34	140	ubiquitous	marker	blood, right adrenal gland, right adrenal gland cortex
CLP1	275	ubiquitous	yes	secondary oocyte, oocyte, epithelium of nasopharynx
EXOSC3	246	ubiquitous	marker	oocyte, secondary oocyte, tendon of biceps brachii
RARS2	255	ubiquitous	marker	ileal mucosa, adrenal tissue, tibialis anterior
VPS53	140	ubiquitous	yes	sural nerve, bone marrow cell, stromal cell of endometrium
TBC1D23	253	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, ileal mucosa
TSEN54	232	ubiquitous	marker	granulocyte, right uterine tube, cerebellar hemisphere
TSEN2	225	ubiquitous	marker	buccal mucosa cell, mucosa of transverse colon, primordial germ cell in gonad
SEPSECS	219	ubiquitous	yes	ileal mucosa, male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver
AMPD2	262	ubiquitous	marker	adenohypophysis, pituitary gland, granulocyte
MINPP1	275	ubiquitous	marker	trabecular bone tissue, tibia, adrenal tissue
CHMP1A	293	ubiquitous	marker	endometrium epithelium, lower esophagus mucosa, mucosa of transverse colon
EXOSC9	285	ubiquitous	marker	secondary oocyte, oocyte, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 26.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VRK1	3,022
RARS2	2,799
EXOSC9	2,532
EXOSC3	2,330
AMPD2	2,024
VPS53	1,921
ATOH1	1,865
CHMP1A	1,793
SEPSECS	1,756
TSEN2	1,088

Intra-cohort edges

A	B	Sources
AMPD2	TSEN54	string_interaction
CHMP1A	TSEN34	string_interaction
CHMP1A	TSEN54	string_interaction
CLP1	TSEN2	biogrid_interaction, intact, string_interaction
CLP1	TSEN34	biogrid_interaction, intact, string_interaction
CLP1	TSEN54	biogrid_interaction, intact, string_interaction
EXOSC3	EXOSC9	biogrid_interaction, intact, string_interaction
EXOSC3	TSEN2	string_interaction
EXOSC3	TSEN34	string_interaction
EXOSC3	TSEN54	string_interaction
EXOSC3	VRK1	string_interaction
EXOSC9	TSEN54	string_interaction
RARS2	TSEN2	string_interaction
RARS2	TSEN34	string_interaction
RARS2	TSEN54	string_interaction
RARS2	VRK1	string_interaction
SEPSECS	TSEN2	string_interaction
SEPSECS	TSEN34	string_interaction
SEPSECS	TSEN54	string_interaction
TSEN2	TSEN34	biogrid_interaction, intact, string_interaction
TSEN2	TSEN54	biogrid_interaction, intact, string_interaction
TSEN2	VRK1	string_interaction
TSEN34	TSEN54	biogrid_interaction, string_interaction
TSEN34	VPS53	string_interaction
TSEN34	VRK1	string_interaction
TSEN54	VRK1	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VRK1	Q99986	26
EXOSC3	Q9NQT5	8
EXOSC9	Q06265	8
SEPSECS	Q9HD40	7
TSEN34	Q9BSV6	6
TSEN54	Q7Z6J9	5
TSEN2	Q8NCE0	5
TBC1D23	Q9NUY8	4
AMPD2	Q01433	4
CHMP1A	Q9HD42	3
CLP1	Q92989	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MINPP1	Q9UNW1	90.42
RARS2	Q5T160	89.18
HEATR5B	Q9P2D3	81.47
VPS53	Q5VIR6	80.86
ATOH1	Q92858	60.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 16 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA processing in the nucleus	4	60.6×	1e-05	TSEN34, CLP1, TSEN54, TSEN2
tRNA processing	3	82.4×	9e-05	TSEN34, TSEN54, TSEN2
mRNA decay by 3’ to 5’ exoribonuclease	2	109.8×	1e-03	EXOSC3, EXOSC9
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	2	97.6×	1e-03	EXOSC3, EXOSC9
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	2	97.6×	1e-03	EXOSC3, EXOSC9
KSRP (KHSRP) binds and destabilizes mRNA	2	97.6×	1e-03	EXOSC3, EXOSC9
ATF4 activates genes in response to endoplasmic reticulum stress	2	62.8×	0.002	EXOSC3, EXOSC9
Nuclear RNA decay	2	47.5×	0.003	EXOSC3, EXOSC9
Synthesis of IPs in the ER lumen	1	878.5×	0.004	MINPP1
Metabolism of RNA	3	9.6×	0.010	TSEN34, TSEN54, TSEN2
Nucleotide salvage	1	87.8×	0.033	AMPD2
Purine salvage	1	67.6×	0.039	AMPD2
Major pathway of rRNA processing in the nucleolus and cytosol	2	9.5×	0.045	EXOSC3, EXOSC9
Initiation of Nuclear Envelope (NE) Reformation	1	46.2×	0.048	VRK1
Processing of Intronless Pre-mRNAs	1	43.9×	0.048	CLP1
Mitochondrial tRNA aminoacylation	1	39.9×	0.050	RARS2
Inositol phosphate metabolism	1	36.6×	0.050	MINPP1
Nuclear Envelope Breakdown	1	35.1×	0.050	VRK1
Metabolism of nucleotides	1	23.1×	0.071	AMPD2
tRNA Aminoacylation	1	22.0×	0.071	RARS2
Retrograde transport at the Trans-Golgi-Network	1	16.9×	0.084	VPS53
RNA Polymerase II Transcription Termination	1	16.9×	0.084	CLP1
Selenoamino acid metabolism	1	15.2×	0.085	SEPSECS
mRNA 3’-end processing	1	15.2×	0.085	CLP1
Metabolism	3	2.7×	0.121	SEPSECS, AMPD2, MINPP1
Selenocysteine synthesis	1	9.2×	0.127	SEPSECS
HCMV Late Events	1	7.6×	0.147	CHMP1A
mRNA Polyadenylation	1	6.8×	0.158	CLP1
Metabolism of amino acids and derivatives	1	5.2×	0.195	SEPSECS
Translation	1	4.8×	0.203	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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tRNA-type intron splice site recognition and cleavage	3	1053.2×	8e-08	TSEN34, TSEN54, TSEN2
tRNA splicing, via endonucleolytic cleavage and ligation	3	263.3×	9e-06	CLP1, TSEN54, TSEN2
exonucleolytic trimming to generate mature 3’-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	2	300.9×	4e-04	EXOSC3, EXOSC9
nuclear polyadenylation-dependent rRNA catabolic process	2	300.9×	4e-04	EXOSC3, EXOSC9
TRAMP-dependent tRNA surveillance pathway	2	300.9×	4e-04	EXOSC3, EXOSC9
U4 snRNA 3’-end processing	2	263.3×	4e-04	EXOSC3, EXOSC9
retrograde transport, endosome to Golgi	3	38.5×	1e-03	VPS53, TBC1D23, HEATR5B
nuclear-transcribed mRNA catabolic process	2	95.8×	0.003	EXOSC3, EXOSC9
mRNA catabolic process	2	62.0×	0.006	EXOSC3, EXOSC9
RNA catabolic process	2	56.9×	0.006	EXOSC3, EXOSC9
auditory receptor cell fate specification	1	1053.2×	0.008	ATOH1
auditory receptor cell fate determination	1	1053.2×	0.008	ATOH1
cyclic purine nucleotide metabolic process	1	1053.2×	0.008	AMPD2
mRNA processing	3	14.8×	0.008	TSEN34, TSEN54, TSEN2
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	526.6×	0.013	SEPSECS
negative regulation of gliogenesis	1	526.6×	0.013	ATOH1
positive regulation of inner ear auditory receptor cell differentiation	1	526.6×	0.013	ATOH1
IMP biosynthetic process	1	351.1×	0.014	AMPD2
arginyl-tRNA aminoacylation	1	351.1×	0.014	RARS2
U1 snRNA 3’-end processing	1	351.1×	0.014	EXOSC9
U5 snRNA 3’-end processing	1	351.1×	0.014	EXOSC9
global gene silencing by mRNA cleavage	1	351.1×	0.014	CLP1
positive regulation of protein localization to chromatin	1	351.1×	0.014	VRK1
RNA processing	2	27.4×	0.014	EXOSC3, EXOSC9
Cajal body organization	1	263.3×	0.016	VRK1
DNA deamination	1	263.3×	0.016	EXOSC3
CUT catabolic process	1	263.3×	0.016	EXOSC3
IMP salvage	1	210.7×	0.018	AMPD2
neuroblast migration	1	210.7×	0.018	ATOH1
obsolete vesicle tethering to Golgi	1	210.7×	0.018	TBC1D23

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 15

Druggability breadth: 5 of 16 evidence-associated genes (31%) 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
ATOH1	0	0
HEATR5B	0	0
VRK1	0	0
TSEN34	0	0
CLP1	0	0
EXOSC3	0	0
RARS2	0	0
VPS53	0	0
TBC1D23	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): 7.

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

Symbol	Assays	Type breakdown
VRK1	74	Binding:74
EXOSC9	7	Binding:7
CHMP1A	6	Binding:6
AMPD2	4	Binding:4
RARS2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TSEN34	4.6.1.16	tRNA-intron lyase
CLP1	2.7.1.78	polynucleotide 5’-hydroxyl-kinase
TSEN54	4.6.1.16	tRNA-intron lyase
TSEN2	4.6.1.16	tRNA-intron lyase
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase
AMPD2	3.5.4.6	AMP deaminase
MINPP1	3.1.3.62	multiple inositol-polyphosphate phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 16; 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	7	VRK1, TSEN34, CLP1, TSEN54, TSEN2, SEPSECS, AMPD2
D	Druggable family + AlphaFold only, no drug	1	MINPP1
E	Difficult family or no structure, no drug	7	ATOH1, HEATR5B, EXOSC3, RARS2, VPS53, TBC1D23, CHMP1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EXOSC3	0	EXOSC9
ATOH1	0	—
HEATR5B	0	—
VRK1	74	—
TSEN34	0	—
CLP1	0	—
RARS2	1	—
VPS53	0	—
TBC1D23	0	—
TSEN54	0	—
TSEN2	0	—
SEPSECS	0	—
AMPD2	4	—
MINPP1	0	—
CHMP1A	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: ATOH1, HEATR5B, VRK1, TSEN34, CLP1, EXOSC3, RARS2, VPS53, TBC1D23, TSEN54, TSEN2, SEPSECS, AMPD2, MINPP1, CHMP1A, EXOSC9