X-linked complex neurodevelopmental disorder

disease

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Summary

X-linked complex neurodevelopmental disorder (MONDO:0100148) is a disease caused by variants in ARX, CNKSR2, GRIA3, and 6 other genes, with 16 cohort genes.

At a glance

Causal genes: ARX (GenCC Definitive), CNKSR2 (GenCC Definitive), GRIA3 (GenCC Definitive), IQSEC2 (GenCC Definitive) (+5 more)
Cohort genes: 16
ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked complex neurodevelopmental disorder
Mondo ID	MONDO:0100148
GARD	0027063
Is cancer (heuristic)	no

Also known as: X-linked complex neurodevelopmental disorder

Data availability: 9 ClinVar variants · 13 GenCC gene-disease records.

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 › X-linked disease › X-linked complex neurodevelopmental disorder

Subtypes (2): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8

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

9 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 1 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3376622	NM_181303.2(NLGN3):c.1978C>T (p.Arg660Cys)	NLGN3	Likely pathogenic	criteria provided, single submitter
207472	NM_006950.3(SYN1):c.1372C>G (p.Gln458Glu)	SYN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779678	NM_001368397.1(FRMPD4):c.2608G>A (p.Val870Ile)	FRMPD4	Uncertain significance	criteria provided, single submitter
3376624	NM_181303.2(NLGN3):c.1373A>T (p.Tyr458Phe)	NLGN3	Uncertain significance	criteria provided, single submitter
989384	NM_181303.2(NLGN3):c.2161C>T (p.Leu721Phe)	NLGN3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4531341	NM_181332.3(NLGN4X):c.1770G>A (p.Trp590Ter)	NLGN4X	Uncertain significance	criteria provided, single submitter
1701599	NM_001282648.2(SLC35A2):c.19+1G>C	SLC35A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
4531331	NM_006306.4(SMC1A):c.2710G>A (p.Glu904Lys)	SMC1A	Uncertain significance	criteria provided, single submitter
4813639	NM_006950.3(SYN1):c.1769del (p.Pro590fs)	SYN1	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 75 · Orphanet: 30 · 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
ARX	Definitive	X-linked	X-linked complex neurodevelopmental disorder	16
CNKSR2	Definitive	X-linked	X-linked complex neurodevelopmental disorder	5
GRIA3	Definitive	X-linked	X-linked complex neurodevelopmental disorder	6
IQSEC2	Definitive	X-linked	intellectual disability, X-linked 1	8
NEXMIF	Definitive	X-linked	X-linked complex neurodevelopmental disorder	5
PCDH19	Definitive	X-linked	X-linked complex neurodevelopmental disorder	6
SLC35A2	Definitive	X-linked	X-linked complex neurodevelopmental disorder	7
WDR45	Definitive	X-linked	X-linked complex neurodevelopmental disorder	8
NLGN3	Strong	X-linked	X-linked complex neurodevelopmental disorder	5
CLIC2	Moderate	X-linked	X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome	6
PJA1	Moderate	X-linked	X-linked complex neurodevelopmental disorder
AGTR2	Supportive	X-linked	non-syndromic X-linked intellectual disability	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC35A2	Orphanet:268973	Isolated focal cortical dysplasia type Ia
SLC35A2	Orphanet:356961	SLC35A2-CDG
PCDH19	Orphanet:33069	Dravet syndrome
PCDH19	Orphanet:714652	PCDH19 clustering epilepsy
ARX	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
ARX	Orphanet:2508	Corpus callosum agenesis-abnormal genitalia syndrome
ARX	Orphanet:3175	X-linked spasticity-intellectual disability-epilepsy syndrome
ARX	Orphanet:364063	Infantile epileptic-dyskinetic encephalopathy
ARX	Orphanet:452	X-linked lissencephaly with abnormal genitalia
ARX	Orphanet:697160	Infantile epileptic spasms syndrome
ARX	Orphanet:777	X-linked non-syndromic intellectual disability
ARX	Orphanet:94083	Partington syndrome
CNKSR2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CNKSR2	Orphanet:777	X-linked non-syndromic intellectual disability
CLIC2	Orphanet:324410	X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome
WDR45	Orphanet:329284	Beta-propeller protein-associated neurodegeneration
WDR45	Orphanet:697160	Infantile epileptic spasms syndrome
IQSEC2	Orphanet:217377	Microduplication Xp11.22p11.23 syndrome
IQSEC2	Orphanet:397933	Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome
IQSEC2	Orphanet:819	Smith-Magenis syndrome
NEXMIF	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
NEXMIF	Orphanet:85277	X-linked intellectual disability, Cantagrel type
AGTR2	Orphanet:777	X-linked non-syndromic intellectual disability
GRIA3	Orphanet:364028	X-linked intellectual disability due to GRIA3 mutations
SMC1A	Orphanet:199	Cornelia de Lange syndrome
SMC1A	Orphanet:220386	Semilobar holoprosencephaly
SMC1A	Orphanet:3095	Atypical Rett syndrome
SMC1A	Orphanet:708203	Intellectual disability-small hands and feet-drug-resistant epilepsy syndrome
SYN1	Orphanet:85294	X-linked epilepsy-learning disabilities-behavior disorders syndrome
FRMPD4	Orphanet:777	X-linked non-syndromic intellectual disability

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
SLC35A2	HGNC:11022	ENSG00000102100	P78381	UDP-galactose translocator	gencc,clinvar
NLGN3	HGNC:14289	ENSG00000196338	Q9NZ94	Neuroligin-3	gencc,clinvar
PCDH19	HGNC:14270	ENSG00000165194	Q8TAB3	Protocadherin-19	gencc
PJA1	HGNC:16648	ENSG00000181191	Q8NG27	E3 ubiquitin-protein ligase Praja-1	gencc
ARX	HGNC:18060	ENSG00000004848	Q96QS3	Homeobox protein ARX	gencc
CNKSR2	HGNC:19701	ENSG00000149970	Q8WXI2	Connector enhancer of kinase suppressor of ras 2	gencc
CLIC2	HGNC:2063	ENSG00000155962	O15247	Chloride intracellular channel protein 2	gencc
WDR45	HGNC:28912	ENSG00000196998	Q9Y484	WD repeat domain phosphoinositide-interacting protein 4	gencc
IQSEC2	HGNC:29059	ENSG00000124313	Q5JU85	IQ motif and SEC7 domain-containing protein 2	gencc
NEXMIF	HGNC:29433	ENSG00000050030	Q5QGS0	Neurite extension and migration factor	gencc
AGTR2	HGNC:338	ENSG00000180772	P50052	Type-2 angiotensin II receptor	gencc
GRIA3	HGNC:4573	ENSG00000125675	P42263	Glutamate receptor 3	gencc
SMC1A	HGNC:11111	ENSG00000072501	Q14683	Structural maintenance of chromosomes protein 1A	clinvar
SYN1	HGNC:11494	ENSG00000008056	P17600	Synapsin-1	clinvar
NLGN4X	HGNC:14287	ENSG00000146938	Q8N0W4	Neuroligin-4, X-linked	clinvar
FRMPD4	HGNC:29007	ENSG00000169933	Q14CM0	FERM and PDZ domain-containing protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC35A2	UDP-galactose translocator	Transports uridine diphosphate galactose (UDP-galactose) from the cytosol into the Golgi apparatus, functioning as an antiporter that exchanges UDP-galactose for UMP.
NLGN3	Neuroligin-3	Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
PCDH19	Protocadherin-19	Calcium-dependent cell-adhesion protein.
PJA1	E3 ubiquitin-protein ligase Praja-1	Has E2-dependent E3 ubiquitin-protein ligase activity.
ARX	Homeobox protein ARX	Transcription factor.
CNKSR2	Connector enhancer of kinase suppressor of ras 2	May function as an adapter protein or regulator of Ras signaling pathways.
CLIC2	Chloride intracellular channel protein 2	In the soluble state, catalyzes glutaredoxin-like thiol disulfide exchange reactions with reduced glutathione as electron donor.
WDR45	WD repeat domain phosphoinositide-interacting protein 4	Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation.
IQSEC2	IQ motif and SEC7 domain-containing protein 2	Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins.
NEXMIF	Neurite extension and migration factor	Involved in neurite outgrowth by regulating cell-cell adhesion via the N-cadherin signaling pathway.
AGTR2	Type-2 angiotensin II receptor	Receptor for angiotensin II, a vasoconstricting peptide.
GRIA3	Glutamate receptor 3	Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid.
SMC1A	Structural maintenance of chromosomes protein 1A	Involved in chromosome cohesion during cell cycle and in DNA repair.
SYN1	Synapsin-1	Neuronal phosphoprotein that coats synaptic vesicles, and binds to the cytoskeleton.
NLGN4X	Neuroligin-4, X-linked	Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
FRMPD4	FERM and PDZ domain-containing protein 4	Positive regulator of dendritic spine morphogenesis and density.

Protein-family classification

Druggable: 1 · Difficult: 6 · Unknown: 9 · Druggable fraction: 0.06

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	4	4.3×	0.046
GPCR	1	1.5×	0.594
Transcription factor	2	1.0×	0.594
Other/Unknown	9	1.0×	0.594

Per-gene assignment

Symbol	Family	Druggable?	InterPro (top 3)
SLC35A2	Other/Unknown	no	Nuc_sug_transpt, EmrE-like
NLGN3	Other/Unknown	no	Nlgn, CarbesteraseB, Carboxylesterase_B_CS
PCDH19	Other/Unknown	no	Cadherin-like_dom, Cadherin_N, Cadherin-like_sf
PJA1	Transcription factor	no	Znf_RING, Znf_RING/FYVE/PHD
ARX	Transcription factor	no	HD, OAR_dom, Homeodomain-like_sf
CNKSR2	Scaffold/PPI	no	PDZ, SAM, PH_domain
CLIC2	Other/Unknown	no	CLIC, Glutathione-S-Trfase_C-like, GST_C_CLIC-2
WDR45	Scaffold/PPI	no	WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
IQSEC2	Scaffold/PPI	no	Sec7_dom, PH_domain, PH-like_dom_sf
NEXMIF	Other/Unknown	no	DUF4683, Nexmif
AGTR2	GPCR	yes	ATII_AT2_rcpt, ATII_rcpt, GPCR_Rhodpsn
GRIA3	Other/Unknown	no	Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
SMC1A	Other/Unknown	no	RecF/RecN/SMC_N, SMC_hinge, SMC
SYN1	Other/Unknown	no	Synapsin, ATP_grasp_subdomain_1, PreATP-grasp_dom_sf
NLGN4X	Other/Unknown	no	Nlgn, CarbesteraseB, Carboxylesterase_B_CS
FRMPD4	Scaffold/PPI	no	FERM_domain, WW_dom, PDZ

Expression context

Cohort genes with no expression data: 0.

15 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
Brodmann (1909) area 23	5
middle temporal gyrus	4
cortical plate	3
prefrontal cortex	2
cerebellar cortex	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
endothelial cell	2
bronchial epithelial cell	1
epithelium of bronchus	1
secondary oocyte	1
ventricular zone	1
entorhinal cortex	1
corpus epididymis	1
ganglionic eminence	1
left ovary	1
ovary	1
right ovary	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC35A2	277	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, epithelium of bronchus
NLGN3	181	broad	marker	cortical plate, ventricular zone, prefrontal cortex
PCDH19	175	broad	marker	cortical plate, entorhinal cortex, middle temporal gyrus
PJA1	271	ubiquitous	marker	cortical plate, ganglionic eminence, corpus epididymis
ARX	162	broad	marker	left ovary, ovary, right ovary
CNKSR2	226	broad	marker	Brodmann (1909) area 23, cerebellar cortex, cerebellar hemisphere
CLIC2	232	broad	marker	calcaneal tendon, colonic epithelium, right lung
WDR45	293	ubiquitous	marker	apex of heart, mucosa of stomach, granulocyte
IQSEC2	236	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
NEXMIF	185	tissue_specific	marker	endothelial cell, Brodmann (1909) area 23, buccal mucosa cell
AGTR2	77	tissue_specific	marker	adrenal tissue, ileal mucosa, smooth muscle tissue
GRIA3	205	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, primary visual cortex
SMC1A	289	ubiquitous	marker	sural nerve, trabecular bone tissue, embryo
SYN1	190	broad	marker	right frontal lobe, right hemisphere of cerebellum, prefrontal cortex
NLGN4X	223	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, dorsal root ganglion
FRMPD4	117	broad	marker	middle temporal gyrus, endothelial cell, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMC1A	5,246
SYN1	3,188
GRIA3	2,380
FRMPD4	2,222
NLGN3	2,122
AGTR2	1,878
NLGN4X	1,823
SLC35A2	1,684
IQSEC2	1,296
WDR45	1,233

Intra-cohort edges

A	B	Sources
ARX	PCDH19	string_interaction
CNKSR2	FRMPD4	string_interaction
IQSEC2	PCDH19	string_interaction
IQSEC2	SMC1A	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMC1A	Q14683	18
AGTR2	P50052	7
FRMPD4	Q14CM0	5
CLIC2	O15247	3
WDR45	Q9Y484	3
NLGN4X	Q8N0W4	3
CNKSR2	Q8WXI2	2
IQSEC2	Q5JU85	2
NLGN3	Q9NZ94	1
PCDH19	Q8TAB3	1
PJA1	Q8NG27	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GRIA3	P42263	83.98
SLC35A2	P78381	80.59
SYN1	P17600	69.86
ARX	Q96QS3	56.51
NEXMIF	Q5QGS0	40.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 64. Enrichment computed across 16 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC35A2 causes congenital disorder of glycosylation 2M (CDG2M)	1	951.7×	0.052	SLC35A2
Neurexins and neuroligins	2	32.8×	0.052	NLGN3, NLGN4X
Activation of AMPA receptors	1	237.9×	0.090	GRIA3
Mitotic Telophase/Cytokinesis	1	119.0×	0.105	SMC1A
Cohesin Loading onto Chromatin	1	95.2×	0.105	SMC1A
Transport of nucleotide sugars	1	95.2×	0.105	SLC35A2
Establishment of Sister Chromatid Cohesion	1	86.5×	0.105	SMC1A
Trafficking of GluR2-containing AMPA receptors	1	56.0×	0.108	GRIA3
Serotonin Neurotransmitter Release Cycle	1	52.9×	0.108	SYN1
Formation of the nephric duct	1	52.9×	0.108	PCDH19
Trafficking of AMPA receptors	1	45.3×	0.108	GRIA3
Unblocking of NMDA receptors, glutamate binding and activation	1	45.3×	0.108	GRIA3
Synaptic adhesion-like molecules	1	45.3×	0.108	GRIA3
Dopamine Neurotransmitter Release Cycle	1	41.4×	0.109	SYN1
Neurotransmitter release cycle	1	36.6×	0.115	SYN1
Signaling by high-kinase activity BRAF mutants	1	26.4×	0.123	CNKSR2
Sensory processing of sound	1	25.7×	0.123	SYN1
Meiosis	1	23.8×	0.123	SMC1A
MAP2K and MAPK activation	1	23.8×	0.123	CNKSR2
Signaling by RAF1 mutants	1	23.2×	0.123	CNKSR2
Transport of vitamins, nucleosides, and related molecules	1	22.7×	0.123	SLC35A2
Signaling by moderate kinase activity BRAF mutants	1	21.1×	0.123	CNKSR2
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	21.1×	0.123	CNKSR2
Signaling downstream of RAS mutants	1	21.1×	0.123	CNKSR2
Ion homeostasis	1	17.0×	0.141	CLIC2
SLC transporter disorders	1	17.0×	0.141	SLC35A2
Reproduction	1	15.9×	0.142	SMC1A
S Phase	1	15.1×	0.142	SMC1A
SUMO E3 ligases SUMOylate target proteins	1	14.9×	0.142	SMC1A
Signaling by BRAF and RAF1 fusions	1	14.2×	0.142	CNKSR2

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
modulation of chemical synaptic transmission	4	45.8×	2e-04	NLGN3, NLGN4X, IQSEC2, GRIA3
synapse organization	3	52.7×	0.001	NLGN3, SYN1, NLGN4X
presynaptic membrane assembly	2	210.7×	0.002	NLGN3, NLGN4X
presynapse assembly	2	150.5×	0.002	NLGN3, NLGN4X
neuron cell-cell adhesion	2	123.9×	0.003	NLGN3, NLGN4X
vocalization behavior	2	110.9×	0.003	NLGN3, NLGN4X
organ growth	2	91.6×	0.004	NLGN4X, ARX
positive regulation of synaptic transmission, glutamatergic	2	78.0×	0.004	NLGN3, IQSEC2
adult behavior	2	58.5×	0.007	NLGN3, NLGN4X
regulation of systemic arterial blood pressure by circulatory renin-angiotensin	1	1053.2×	0.012	AGTR2
brain renin-angiotensin system	1	526.6×	0.012	AGTR2
G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger	1	526.6×	0.012	AGTR2
embryonic olfactory bulb interneuron precursor migration	1	526.6×	0.012	ARX
regulation of metanephros size	1	526.6×	0.012	AGTR2
UDP-galactose transmembrane transport	1	526.6×	0.012	SLC35A2
response to DNA damage checkpoint signaling	1	526.6×	0.012	SMC1A
learning	2	35.1×	0.012	NLGN3, NLGN4X
social behavior	2	34.0×	0.012	NLGN3, NLGN4X
neuron development	2	31.9×	0.012	SYN1, ARX
positive regulation of synapse assembly	2	30.5×	0.012	NLGN3, IQSEC2
synapse assembly	2	28.9×	0.012	NLGN3, NLGN4X
angiotensin-mediated vasodilation involved in regulation of systemic arterial blood pressure	1	351.1×	0.014	AGTR2
positive regulation of synapse structural plasticity	1	351.1×	0.014	FRMPD4
positive regulation of metanephric glomerulus development	1	351.1×	0.014	AGTR2
postsynaptic specialization organization	1	351.1×	0.014	CNKSR2
cerebral cortex tangential migration	1	263.3×	0.015	ARX
establishment of meiotic sister chromatid cohesion	1	263.3×	0.015	SMC1A
negative regulation of neurotrophin TRK receptor signaling pathway	1	263.3×	0.015	AGTR2
rhythmic synaptic transmission	1	263.3×	0.015	NLGN3
epithelial cell fate commitment	1	263.3×	0.015	ARX

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 13

Druggability breadth: 5 of 16 evidence-associated genes (31%) 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
AGTR2	IRBESARTAN
GRIA3	PERAMPANEL
SMC1A	SELUMETINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AGTR2	19	4
GRIA3	7	4
SMC1A	2	4
SLC35A2	0	0
NLGN3	0	0
PCDH19	0	0
PJA1	0	0
ARX	0	0
CNKSR2	0	0
CLIC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IRBESARTAN	4	AGTR2
LOSARTAN	4	AGTR2
SARALASIN	4	AGTR2
LOSARTAN POTASSIUM	4	AGTR2
CANDESARTAN CILEXETIL	4	AGTR2
TELMISARTAN	4	AGTR2
OLMESARTAN MEDOXOMIL	4	AGTR2
DICLOFENAC	4	AGTR2
AZILSARTAN MEDOXOMIL	4	AGTR2
ANGIOTENSIN II	4	AGTR2
BENAZEPRIL	4	AGTR2
MICONAZOLE	4	AGTR2
PERAMPANEL	4	GRIA3
CYCLOTHIAZIDE	4	GRIA3
SELUMETINIB	4	SMC1A
CANDESARTAN	3	AGTR2
OLMESARTAN	3	AGTR2
ANGIOTENSIN	3	AGTR2
GLUTAMIC ACID	3	GRIA3
FORASARTAN	2	AGTR2
PRATOSARTAN	2	AGTR2
TASOSARTAN	2	AGTR2
OLODANRIGAN	2	AGTR2
TEZAMPANEL ANHYDROUS	2	GRIA3
SELFOTEL	2	GRIA3
KAINIC ACID	2	GRIA3
FARAMPATOR	2	GRIA3
MOLIBRESIB	2	SMC1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
AGTR2	244	Binding:188, Functional:56
GRIA3	126	Binding:113, Functional:13
SMC1A	10	Binding:10
SLC35A2	1	ADMET:1
CNKSR2	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
AGTR2	244
GRIA3	126

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

28 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)
IRBESARTAN	4	AGTR2
LOSARTAN	4	AGTR2
SARALASIN	4	AGTR2
LOSARTAN POTASSIUM	4	AGTR2
CANDESARTAN CILEXETIL	4	AGTR2
TELMISARTAN	4	AGTR2
OLMESARTAN MEDOXOMIL	4	AGTR2
DICLOFENAC	4	AGTR2
AZILSARTAN MEDOXOMIL	4	AGTR2
ANGIOTENSIN II	4	AGTR2
BENAZEPRIL	4	AGTR2
MICONAZOLE	4	AGTR2
PERAMPANEL	4	GRIA3
CYCLOTHIAZIDE	4	GRIA3
SELUMETINIB	4	SMC1A
CANDESARTAN	3	AGTR2
OLMESARTAN	3	AGTR2
ANGIOTENSIN	3	AGTR2
GLUTAMIC ACID	3	GRIA3
FORASARTAN	2	AGTR2
PRATOSARTAN	2	AGTR2
TASOSARTAN	2	AGTR2
OLODANRIGAN	2	AGTR2
TEZAMPANEL ANHYDROUS	2	GRIA3
SELFOTEL	2	GRIA3
KAINIC ACID	2	GRIA3
FARAMPATOR	2	GRIA3
MOLIBRESIB	2	SMC1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	AGTR2, GRIA3, SMC1A
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	13	SLC35A2, NLGN3, PCDH19, PJA1, ARX, CNKSR2, CLIC2, WDR45, IQSEC2, NEXMIF (+3 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IQSEC2	0	SMC1A
SLC35A2	1	—
NLGN3	0	—
PCDH19	0	—
PJA1	0	—
ARX	0	—
CNKSR2	1	—
CLIC2	0	—
WDR45	0	—
NEXMIF	0	—
SYN1	0	—
NLGN4X	0	—
FRMPD4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: SLC35A2, NLGN3, PCDH19, PJA1, ARX, CNKSR2, CLIC2, WDR45, IQSEC2, NEXMIF, AGTR2, GRIA3, SMC1A, SYN1, NLGN4X, FRMPD4
Associated genes: ARHGEF9, CDK16, FAAH2, FTSJ1, HNRNPH2, PTCHD1, SHROOM4, SLITRK2, THOC2, UPF3B, ZDHHC15, ZNF711