Gnb5-related intellectual disability-cardiac arrhythmia syndrome

Summary

Gnb5-related intellectual disability-cardiac arrhythmia syndrome (MONDO:0014953) is a disease caused by GNB5 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GNB5 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 27
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001626	Abnormality of the cardiovascular system	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001662	Bradycardia	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0005155	Ventricular escape rhythm	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0011704	Sick sinus syndrome	Frequent (30-79%)
HP:0000546	Retinal degeneration	Occasional (5-29%)
HP:0000563	Keratoconus	Occasional (5-29%)
HP:0000817	Reduced eye contact	Occasional (5-29%)
HP:0001655	Patent foramen ovale	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0007010	Poor fine motor coordination	Occasional (5-29%)
HP:0012248	Prolonged PR interval	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	gnb5-related intellectual disability-cardiac arrhythmia syndrome
Mondo ID	MONDO:0014953
OMIM	617173
Orphanet	542306
DOID	DOID:0081008
UMLS	C5568877
MedGen	1800300
GARD	0017982
Is cancer (heuristic)	no

Also known as: IDDCA · intellectual developmental disorder with cardiac arrhythmia · intellectual developmental disorder with cardiac arrhythmia; IDDCA

Data availability: 27 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

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 › gnb5-related intellectual disability-cardiac arrhythmia syndrome

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, 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, NAD(P)HX dehydratase deficiency, 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

27 retrieved; paginated sample, class counts are floors:

13 pathogenic, 6 likely pathogenic, 5 uncertain significance, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1326436	NM_016194.4(GNB5):c.61C>T (p.Arg21Ter)	CERNA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210290	NM_016194.4(GNB5):c.262del (p.Glu88fs)	GNB5	Pathogenic	criteria provided, multiple submitters, no conflicts
1685857	NM_016194.4(GNB5):c.1160G>C (p.Trp387Ser)	GNB5	Pathogenic	criteria provided, single submitter
1694471	NM_016194.4(GNB5):c.239-2A>C	GNB5	Pathogenic	criteria provided, single submitter
254029	NM_016194.4(GNB5):c.368C>T (p.Ser123Leu)	GNB5	Pathogenic	criteria provided, multiple submitters, no conflicts
2575916	NM_016194.4(GNB5):c.368C>A (p.Ser123Ter)	GNB5	Pathogenic	no assertion criteria provided
2575917	NM_016194.4(GNB5):c.458G>A (p.Cys153Tyr)	GNB5	Pathogenic	no assertion criteria provided
2575918	NM_016194.4(GNB5):c.863G>A (p.Arg288Gln)	GNB5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2575919	NM_016194.4(GNB5):c.481del (p.Ala161fs)	GNB5	Pathogenic	no assertion criteria provided
268098	NM_016194.4(GNB5):c.375G>A (p.Gln125=)	GNB5	Pathogenic	no assertion criteria provided
268100	NM_016194.4(GNB5):c.375+1G>T	GNB5	Pathogenic	criteria provided, single submitter
268102	NM_016194.4(GNB5):c.1032C>G (p.Tyr344Ter)	GNB5	Pathogenic	criteria provided, multiple submitters, no conflicts
4073558	NM_016194.4(GNB5):c.514del (p.Ser172fs)	GNB5	Pathogenic	criteria provided, single submitter
4081908	NM_016194.4(GNB5):c.640_641delinsC (p.Ser214fs)	GNB5	Pathogenic	no assertion criteria provided
426541	NM_016194.4(GNB5):c.348_352del (p.Asp116fs)	GNB5	Pathogenic	criteria provided, single submitter
450608	NM_016194.4(GNB5):c.1032C>A (p.Tyr344Ter)	GNB5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4278465	NM_014862.4(ARNT2):c.147-1G>A	ARNT2	Likely pathogenic	criteria provided, single submitter
268099	NM_016194.4(GNB5):c.1120C>T (p.Arg374Ter)	GNB5	Likely pathogenic	criteria provided, single submitter
3256586	NM_016194.4(GNB5):c.819C>A (p.Cys273Ter)	GNB5	Likely pathogenic	criteria provided, single submitter
3385342	NM_016194.4(GNB5):c.1009+1G>C	GNB5	Likely pathogenic	criteria provided, single submitter
4073556	NM_016194.4(GNB5):c.628-6G>A	GNB5	Likely pathogenic	criteria provided, single submitter
977622	NM_016194.4(GNB5):c.368C>G (p.Ser123Trp)	GNB5	Likely pathogenic	criteria provided, single submitter
1030537	NM_016194.4(GNB5):c.1132G>A (p.Asp378Asn)	GNB5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033806	NM_016194.4(GNB5):c.790A>G (p.Met264Val)	GNB5	Uncertain significance	criteria provided, single submitter
1709824	NM_016194.4(GNB5):c.292A>G (p.Arg98Gly)	GNB5	Uncertain significance	criteria provided, multiple submitters, no conflicts
268101	NM_016194.4(GNB5):c.375+3A>G	GNB5	Uncertain significance	criteria provided, single submitter
3385341	NM_016194.4(GNB5):c.1177-1G>T	GNB5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
GNB5	Strong	Autosomal recessive	language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNB5	Orphanet:542306	GNB5-related intellectual disability-cardiac arrhythmia syndrome
ARNT2	Orphanet:3157	Septo-optic dysplasia spectrum

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNB5	HGNC:4401	ENSG00000069966	O14775	Guanine nucleotide-binding protein subunit beta-5	gencc,clinvar
ARNT2	HGNC:16876	ENSG00000172379	Q9HBZ2	Aryl hydrocarbon receptor nuclear translocator 2	clinvar
CERNA1	HGNC:52664	ENSG00000259577		competing endogenous lncRNA 1 for miR-4707-5p and miR-4767	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNB5	Guanine nucleotide-binding protein subunit beta-5	Enhances GTPase-activating protein (GAP) activity of regulator of G protein signaling (RGS) proteins, such as RGS7 and RGS9, hence involved in the termination of the signaling initiated by the G protein coupled receptors (GPCRs) by acceler…
ARNT2	Aryl hydrocarbon receptor nuclear translocator 2	Transcription factor that plays a role in the development of the hypothalamo-pituitary axis, postnatal brain growth, and visual and renal function.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNB5	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
ARNT2	Transcription factor	no		PAS, Nuc_translocat, PAC
CERNA1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	2
middle temporal gyrus	2
cerebellar hemisphere	1
frontal pole	1
lateral globus pallidus	1
male germ line stem cell (sensu Vertebrata) in testis	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNB5	279	ubiquitous	marker	middle temporal gyrus, endothelial cell, cerebellar hemisphere
ARNT2	246	ubiquitous	marker	lateral globus pallidus, middle temporal gyrus, frontal pole
CERNA1	158	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, endothelial cell, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNB5	2,987
ARNT2	1,294
CERNA1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNB5	O14775	32

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARNT2	Q9HBZ2	59.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 3 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
Aryl hydrocarbon receptor signalling	1	951.7×	0.012	ARNT2
Cytochrome P450 - arranged by substrate type	1	356.9×	0.012	ARNT2
G beta:gamma signalling through BTK	1	317.2×	0.012	GNB5
Prostacyclin signalling through prostacyclin receptor	1	300.5×	0.012	GNB5
G beta:gamma signalling through PLC beta	1	285.5×	0.012	GNB5
G beta:gamma signalling through CDC42	1	285.5×	0.012	GNB5
Transcriptional Regulation by NPAS4	1	285.5×	0.012	ARNT2
Presynaptic function of Kainate receptors	1	271.9×	0.012	GNB5
Xenobiotics	1	248.3×	0.012	ARNT2
ADP signalling through P2Y purinoceptor 12	1	248.3×	0.012	GNB5
NPAS4 regulates expression of target genes	1	248.3×	0.012	ARNT2
G-protein activation	1	237.9×	0.012	GNB5
Thromboxane signalling through TP receptor	1	237.9×	0.012	GNB5
ADP signalling through P2Y purinoceptor 1	1	228.4×	0.012	GNB5
G beta:gamma signalling through PI3Kgamma	1	219.6×	0.012	GNB5
Activation of G protein gated Potassium channels	1	196.9×	0.012	GNB5
Endogenous sterols	1	196.9×	0.012	ARNT2
Adrenaline,noradrenaline inhibits insulin secretion	1	196.9×	0.012	GNB5
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	196.9×	0.012	GNB5
Thrombin signalling through proteinase activated receptors (PARs)	1	178.4×	0.012	GNB5
Glucagon-type ligand receptors	1	173.0×	0.012	GNB5
Inactivation, recovery and regulation of the phototransduction cascade	1	158.6×	0.013	GNB5
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	150.3×	0.013	GNB5
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	132.8×	0.013	GNB5
Vasopressin regulates renal water homeostasis via Aquaporins	1	132.8×	0.013	GNB5
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.013	GNB5
GPER1 signaling	1	124.1×	0.013	GNB5
G alpha (z) signalling events	1	116.5×	0.013	GNB5
Phase I - Functionalization of compounds	1	109.8×	0.014	ARNT2
Ca2+ pathway	1	89.2×	0.016	GNB5

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
dark adaptation	1	4213.0×	0.003	GNB5
light adaption	1	2808.7×	0.003	GNB5
G protein-coupled dopamine receptor signaling pathway	1	936.2×	0.006	GNB5
response to estradiol	1	99.1×	0.040	ARNT2
central nervous system development	1	57.7×	0.055	ARNT2
response to hypoxia	1	47.9×	0.055	ARNT2
brain development	1	39.8×	0.055	ARNT2
in utero embryonic development	1	36.0×	0.055	ARNT2
G protein-coupled receptor signaling pathway	1	18.1×	0.083	GNB5
negative regulation of apoptotic process	1	17.4×	0.083	ARNT2
positive regulation of cell population proliferation	1	16.8×	0.083	ARNT2
regulation of DNA-templated transcription	1	15.8×	0.083	ARNT2
positive regulation of DNA-templated transcription	1	14.0×	0.087	ARNT2
signal transduction	1	8.0×	0.138	GNB5
positive regulation of transcription by RNA polymerase II	1	7.4×	0.139	ARNT2
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ARNT2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
GNB5	0	0
ARNT2	0	0
CERNA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
E	Difficult family or no structure, no drug	3	GNB5, ARNT2, CERNA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GNB5	0	—
ARNT2	0	—
CERNA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.