PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome

Summary

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome (MONDO:1060108) is a disease with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 471
• Phenotypes (HPO): 86

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

86 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001344	Absent speech	Very frequent (80-99%)
HP:0002136	Broad-based gait	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0010862	Delayed fine motor development	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000549	Abnormal conjugate eye movement	Frequent (30-79%)
HP:0000977	Soft skin	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001262	Excessive daytime somnolence	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002045	Hypothermia	Frequent (30-79%)
HP:0002104	Apnea	Frequent (30-79%)
HP:0002267	Exaggerated startle response	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0002791	Hypoventilation	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0005957	Breathing dysregulation	Frequent (30-79%)
HP:0010536	Central sleep apnea	Frequent (30-79%)
HP:0010863	Receptive language delay	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012171	Stereotypical hand wringing	Frequent (30-79%)
HP:0100247	Recurrent singultus	Frequent (30-79%)
HP:0100512	Low levels of vitamin D	Frequent (30-79%)
HP:0100660	Dyskinesia	Frequent (30-79%)
HP:0000119	Abnormality of the genitourinary system	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000293	Full cheeks	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000818	Abnormality of the endocrine system	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0002002	Deep philtrum	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002058	Myopathic facies	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome
Mondo ID	MONDO:1060108
Orphanet	438213
UMLS	C4015357
MedGen	863794
GARD	0027440
Is cancer (heuristic)	no

Also known as: PURA syndrome · PURA-related neurodevelopmental disorders

Data availability: 471 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (2): PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation, severe neonatal hypotonia-seizures-encephalopathy syndrome due to 5q31.3 microdeletion

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

471 retrieved; paginated sample, class counts are floors:

162 likely benign, 128 uncertain significance, 81 pathogenic, 43 likely pathogenic, 19 benign, 17 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 8 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1452546	NM_005859.5(PURA):c.387dup (p.Pro130fs)	LOC129994826	Pathogenic	criteria provided, single submitter
2022803	NM_005859.5(PURA):c.380dup (p.Ser127fs)	LOC129994826	Pathogenic	criteria provided, single submitter
1330185	GRCh37/hg19 5q31.2-31.3(chr5:139493717-140517454)x1	PCDHB@	Pathogenic	criteria provided, single submitter
1053368	NM_005859.5(PURA):c.895dup (p.Gln299fs)	PURA	Pathogenic	criteria provided, single submitter
1068656	NM_005859.5(PURA):c.647_660del (p.Ala216fs)	PURA	Pathogenic	criteria provided, single submitter
1070477	NM_005859.5(PURA):c.502dup (p.Leu168fs)	PURA	Pathogenic	criteria provided, single submitter
1299583	NM_005859.5(PURA):c.531del (p.Pro178fs)	PURA	Pathogenic	criteria provided, multiple submitters, no conflicts
1302015	NM_005859.5(PURA):c.406C>T (p.Gln136Ter)	PURA	Pathogenic	criteria provided, single submitter
1313493	NM_005859.5(PURA):c.478A>G (p.Lys160Glu)	PURA	Pathogenic	criteria provided, multiple submitters, no conflicts
1334710	NM_005859.5(PURA):c.530_531dup (p.Pro178fs)	PURA	Pathogenic	criteria provided, single submitter
1335851	NM_005859.5(PURA):c.692T>G (p.Phe231Cys)	PURA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1360182	NM_005859.5(PURA):c.310dup (p.Met104fs)	PURA	Pathogenic	criteria provided, single submitter
1451955	NM_005859.5(PURA):c.389del (p.Pro130fs)	PURA	Pathogenic	criteria provided, single submitter
156403	NM_005859.5(PURA):c.812_814del (p.Phe271del)	PURA	Pathogenic	criteria provided, multiple submitters, no conflicts
156404	NM_005859.5(PURA):c.307_308del (p.Ser103fs)	PURA	Pathogenic	criteria provided, multiple submitters, no conflicts
156405	NM_005859.5(PURA):c.556C>T (p.Gln186Ter)	PURA	Pathogenic	no assertion criteria provided
156406	NM_005859.5(PURA):c.289A>G (p.Lys97Glu)	PURA	Pathogenic	criteria provided, single submitter
156408	NM_005859.5(PURA):c.363C>G (p.Tyr121Ter)	PURA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156411	NM_005859.5(PURA):c.265G>C (p.Ala89Pro)	PURA	Pathogenic	criteria provided, multiple submitters, no conflicts
156413	NM_005859.5(PURA):c.596G>C (p.Arg199Pro)	PURA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686114	NM_005859.5(PURA):c.169G>T (p.Glu57Ter)	PURA	Pathogenic	criteria provided, multiple submitters, no conflicts
1686115	NM_005859.5(PURA):c.512G>C (p.Arg171Pro)	PURA	Pathogenic	criteria provided, single submitter
1686116	NM_005859.5(PURA):c.629del (p.Gly210fs)	PURA	Pathogenic	criteria provided, single submitter
1686117	NM_005859.5(PURA):c.715A>T (p.Lys239Ter)	PURA	Pathogenic	criteria provided, single submitter
1691853	NM_005859.5(PURA):c.235C>T (p.Gln79Ter)	PURA	Pathogenic	criteria provided, single submitter
1699218	NM_005859.5(PURA):c.74del (p.Gly25fs)	PURA	Pathogenic	criteria provided, single submitter
1699399	NM_005859.5(PURA):c.426_427dup (p.Leu143fs)	PURA	Pathogenic	criteria provided, single submitter
1706638	NM_005859.5(PURA):c.98dup (p.Gly34fs)	PURA	Pathogenic	criteria provided, single submitter
1805900	NM_005859.5(PURA):c.217T>G (p.Phe73Val)	PURA	Pathogenic	criteria provided, single submitter
189317	NM_005859.5(PURA):c.726_727del (p.Phe243fs)	PURA	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
PURA	Orphanet:314655	Severe neonatal hypotonia-seizures-encephalopathy syndrome due to 5q31.3 microdeletion
PURA	Orphanet:438216	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HARS2	HGNC:4817	ENSG00000112855	P49590	Histidine–tRNA ligase, mitochondrial	clinvar
PCDHB@	HGNC:8679			protocadherin beta cluster	clinvar
PCDHGA9	HGNC:8707	ENSG00000261934	Q9Y5G4	Protocadherin gamma-A9	clinvar
PURA	HGNC:9701	ENSG00000185129	Q00577	Transcriptional activator protein Pur-alpha	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).
PCDHGA9	Protocadherin gamma-A9	Potential calcium-dependent cell-adhesion protein.
PURA	Transcriptional activator protein Pur-alpha	This is a probable transcription activator that specifically binds the purine-rich single strand of the PUR element located upstream of the MYC gene.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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	3.0×	0.404
Other/Unknown	3	1.3×	0.404

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
PCDHB@	Other/Unknown	no
PCDHGA9	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf
PURA	Other/Unknown	no		PUR-bd_fam

Expression context

Cohort genes with no expression data: 1.

3 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)	3
unknown	1

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
cortical plate	1
ganglionic eminence	1
stromal cell of endometrium	1
Brodmann (1909) area 23	1
choroid plexus epithelium	1
middle temporal gyrus	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
PCDHB@
PCDHGA9	151	broad	marker	stromal cell of endometrium, cortical plate, ganglionic eminence
PURA	295	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HARS2	2,703
PURA	1,483
PCDHGA9	346
PCDHB@	0

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PURA	Q00577	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HARS2	P49590	88.44
PCDHGA9	Q9Y5G4	75.80

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 4 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 3 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	2808.7×	0.004	HARS2
dendritic transport of messenger ribonucleoprotein complex	1	1872.4×	0.004	PURA
lymphocyte proliferation	1	802.5×	0.005	PURA
nervous system development	2	30.6×	0.005	PCDHGA9, PURA
tRNA aminoacylation for protein translation	1	280.9×	0.010	HARS2
DNA replication initiation	1	208.1×	0.011	PURA
epithelial cell proliferation	1	104.0×	0.019	PURA
mitochondrial translation	1	57.9×	0.030	HARS2
homophilic cell-cell adhesion	1	46.8×	0.033	PCDHGA9
translation	1	34.2×	0.040	HARS2
cell adhesion	1	12.5×	0.099	PCDHGA9
positive regulation of cell population proliferation	1	11.2×	0.101	PURA
negative regulation of transcription by RNA polymerase II	1	5.9×	0.172	PURA
regulation of transcription by RNA polymerase II	1	3.9×	0.236	PURA

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
PCDHB@	0	0
PCDHGA9	0	0
PURA	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: 4; 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	3	PCDHB@, PCDHGA9, PURA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HARS2	0	—
PCDHB@	0	—
PCDHGA9	0	—
PURA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.