NAD(P)HX dehydratase deficiency

Summary

NAD(P)HX dehydratase deficiency (MONDO:0034121) is a disease caused by NAXD (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NAXD (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	NAD(P)HX dehydratase deficiency
Mondo ID	MONDO:0034121
OMIM	618321
Orphanet	555402
UMLS	C5193026
MedGen	1681210
GARD	0017990
Is cancer (heuristic)	no

Also known as: PEBEL2

Data availability: 29 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

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 › NAD(P)HX dehydratase deficiency

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

29 retrieved; paginated sample, class counts are floors:

8 likely pathogenic, 8 pathogenic, 7 uncertain significance, 4 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703005	NC_000013.11:g.110615008_110622534del	LOC130010118	Pathogenic	no assertion criteria provided
1703002	NM_001242882.2(NAXD):c.318C>G (p.Ile106Met)	NAXD	Pathogenic	no assertion criteria provided
1703003	NM_001242882.2(NAXD):c.102_103del (p.Thr35fs)	NAXD	Pathogenic	no assertion criteria provided
617756	NM_001242882.2(NAXD):c.839+1G>T	NAXD	Pathogenic	no assertion criteria provided
617757	NM_001242882.2(NAXD):c.948_949insTT (p.Ala317fs)	NAXD	Pathogenic	no assertion criteria provided
617758	NM_001242882.2(NAXD):c.187G>A (p.Gly63Ser)	NAXD	Pathogenic	no assertion criteria provided
617759	NM_001242882.2(NAXD):c.54_57del (p.Ala20fs)	NAXD	Pathogenic	criteria provided, multiple submitters, no conflicts
978059	NM_001242882.2(NAXD):c.44del (p.Arg15fs)	NAXD	Pathogenic	no assertion criteria provided
4057251	NM_001260.3(CDK8):c.563C>G (p.Ala188Gly)	CDK8	Likely pathogenic	criteria provided, single submitter
1683695	NM_001242882.2(NAXD):c.715C>T (p.Gln239Ter)	NAXD	Likely pathogenic	criteria provided, single submitter
1699273	NM_001242882.2(NAXD):c.441+3A>G	NAXD	Likely pathogenic	criteria provided, single submitter
2444094	NM_001242882.2(NAXD):c.442-1G>A	NAXD	Likely pathogenic	criteria provided, single submitter
3341304	NM_001242882.2(NAXD):c.514C>T (p.Gln172Ter)	NAXD	Likely pathogenic	criteria provided, single submitter
3376781	NM_001242882.2(NAXD):c.848del (p.Pro283fs)	NAXD	Likely pathogenic	criteria provided, single submitter
3377366	NM_001242882.2(NAXD):c.704C>T (p.Ser235Phe)	NAXD	Likely pathogenic	criteria provided, single submitter
3891809	NM_001242882.2(NAXD):c.238A>T (p.Lys80Ter)	NAXD	Likely pathogenic	criteria provided, single submitter
1575446	NM_001242882.2(NAXD):c.521C>T (p.Pro174Leu)	NAXD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1878595	NM_001242882.2(NAXD):c.591C>G (p.Asp197Glu)	NAXD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1906889	NM_001242882.2(NAXD):c.794_798dup (p.Val267fs)	NAXD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
617755	NM_001242882.2(NAXD):c.922C>T (p.Arg308Cys)	NAXD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031245	NM_001242882.2(NAXD):c.181G>C (p.Val61Leu)	NAXD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031246	NM_001242882.2(NAXD):c.923G>A (p.Arg308His)	NAXD	Uncertain significance	criteria provided, single submitter
1031247	NM_001242882.2(NAXD):c.46G>A (p.Val16Ile)	NAXD	Uncertain significance	criteria provided, single submitter
1362727	NM_001242882.2(NAXD):c.671C>T (p.Thr224Met)	NAXD	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434040	NM_001242882.2(NAXD):c.736G>A (p.Glu246Lys)	NAXD	Uncertain significance	criteria provided, single submitter
3065704	NM_001242882.2(NAXD):c.862G>A (p.Ala288Thr)	NAXD	Uncertain significance	criteria provided, single submitter
3256536	NM_001242882.2(NAXD):c.269G>T (p.Cys90Phe)	NAXD	Uncertain significance	criteria provided, single submitter
1165146	NM_001242882.2(NAXD):c.840-58C>T	NAXD	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1644883	NM_001242882.2(NAXD):c.102T>A (p.Asn34Lys)	NAXD	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
NAXD	Definitive	Autosomal recessive	NAD(P)HX dehydratase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NAXD	Orphanet:555402	NAD(P)HX dehydratase deficiency
CDK8	Orphanet:528084	Non-specific syndromic intellectual disability

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
NAXD	HGNC:25576	ENSG00000213995	Q8IW45	ATP-dependent (S)-NAD(P)H-hydrate dehydratase	gencc,clinvar
CDK8	HGNC:1779	ENSG00000132964	P49336	Cyclin-dependent kinase 8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NAXD	ATP-dependent (S)-NAD(P)H-hydrate dehydratase	Catalyzes the dehydration of the S-form of NAD(P)HX at the expense of ATP, which is converted to ADP.
CDK8	Cyclin-dependent kinase 8	Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes.

Protein-family classification

Druggable: 2 · 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
Kinase	2	27.7×	0.001

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NAXD	Kinase	yes	4.2.1.93	CARKD, Ribokinase-like
CDK8	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardia of stomach	1
left ovary	1
right adrenal gland cortex	1
adrenal tissue	1
buccal mucosa cell	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NAXD	292	ubiquitous	marker	cardia of stomach, left ovary, right adrenal gland cortex
CDK8	289	ubiquitous	yes	adrenal tissue, buccal mucosa cell, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDK8	2,827
NAXD	1,493

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDK8	P49336	36

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NAXD	Q8IW45	89.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	203.9×	0.025	CDK8
Signaling by NOTCH1 in Cancer	1	203.9×	0.025	CDK8
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	203.9×	0.025	CDK8
Nicotinate metabolism	1	196.9×	0.025	NAXD
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	184.2×	0.025	CDK8
Signaling by NOTCH1	1	178.4×	0.025	CDK8
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	154.3×	0.025	CDK8
NOTCH1 Intracellular Domain Regulates Transcription	1	119.0×	0.025	CDK8
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.025	CDK8
Signaling by TGF-beta Receptor Complex	1	100.2×	0.025	CDK8
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.025	CDK8
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.025	CDK8
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.025	CDK8
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.025	CDK8
Signaling by NOTCH	1	87.8×	0.025	CDK8
RSV-host interactions	1	78.2×	0.025	CDK8
Adipogenesis	1	78.2×	0.025	CDK8
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.025	CDK8
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.026	CDK8
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.027	CDK8
Signaling by TGFB family members	1	57.7×	0.029	CDK8
PPARA activates gene expression	1	47.2×	0.034	CDK8
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.037	CDK8
Epigenetic regulation of gene expression	1	35.7×	0.041	CDK8
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.049	CDK8
Metabolism of lipids	1	15.8×	0.083	CDK8
Viral Infection Pathways	1	15.4×	0.083	CDK8
Infectious disease	1	12.4×	0.099	CDK8
RNA Polymerase II Transcription	1	11.3×	0.105	CDK8
Gene expression (Transcription)	1	8.9×	0.127	CDK8

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
nicotinamide nucleotide metabolic process	1	4213.0×	5e-04	NAXD
metabolite repair	1	4213.0×	5e-04	NAXD
nicotinate metabolic process	1	702.2×	0.002	NAXD
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	CDK8

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
CDK8	SORAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK8	23	4
NAXD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SORAFENIB	4	CDK8
PONATINIB	4	CDK8
QUIZARTINIB	4	CDK8
VATALANIB	3	CDK8
DINACICLIB	3	CDK8
LINIFANIB	3	CDK8
FASUDIL	3	CDK8
ALVOCIDIB	3	CDK8
ALISERTIB	3	CDK8
LESTAURTINIB	3	CDK8
INDIRUBIN	2	CDK8
DORAMAPIMOD	2	CDK8
FORETINIB	2	CDK8
ILORASERTIB	2	CDK8
VORUCICLIB	2	CDK8
CT-7001	2	CDK8
CP-724714	2	CDK8
SENEXIN B	1	CDK8
SEL-120 FREE BASE	1	CDK8
BMS-387032	1	CDK8
SEL-120	1	CDK8
SNS-314	1	CDK8
AST-487	1	CDK8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CDK8	509	Binding:499, Functional:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NAXD	4.2.1.93	ATP-dependent NAD(P)H-hydrate dehydratase
CDK8	2.7.11.22, 2.7.11.23	cyclin-dependent kinase, [RNA-polymerase]-subunit kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CDK8	509

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

23 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)
SORAFENIB	4	CDK8
PONATINIB	4	CDK8
QUIZARTINIB	4	CDK8
VATALANIB	3	CDK8
DINACICLIB	3	CDK8
LINIFANIB	3	CDK8
FASUDIL	3	CDK8
ALVOCIDIB	3	CDK8
ALISERTIB	3	CDK8
LESTAURTINIB	3	CDK8
INDIRUBIN	2	CDK8
DORAMAPIMOD	2	CDK8
FORETINIB	2	CDK8
ILORASERTIB	2	CDK8
VORUCICLIB	2	CDK8
CT-7001	2	CDK8
CP-724714	2	CDK8
SENEXIN B	1	CDK8
SEL-120 FREE BASE	1	CDK8
BMS-387032	1	CDK8
SEL-120	1	CDK8
SNS-314	1	CDK8
AST-487	1	CDK8

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDK8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	NAXD
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)
NAXD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.