non-syndromic X-linked intellectual disability

disease

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Also known as intellectual disability, nonsyndromic, X-linkedintellectual disability, X-linked, nonsyndromicisolated X-linked intellectual disabilitymental retardation, nonsyndromic, X-linkedmental retardation, X-linked, nonsyndromicnon-specific X-linked intellectual disabilitynon-syndromic intellectual disability, X-linkednonsyndromic X-linked intellectual disabilityX-linked non-specific intellectual disabilityX-linked non-syndromic intellectual disability

Summary

non-syndromic X-linked intellectual disability (MONDO:0019181) is a disease (an umbrella term covering 52 Mondo subtypes) caused by variants in RLIM and PTCHD1, with 36 cohort genes. The dominant Reactome pathway is RHOU GTPase cycle (3 cohort genes).

At a glance

Prevalence: Unknown (Worldwide)
Causal genes: RLIM (GenCC Definitive), PTCHD1 (GenCC Strong)
Umbrella term: 52 Mondo subtypes
Cohort genes: 36
ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	non-syndromic X-linked intellectual disability
Mondo ID	MONDO:0019181
MeSH	C564490
OMIM	309530
Orphanet	777
DOID	DOID:0050776
UMLS	C3501611
MedGen	502019
GARD	0018640
Is cancer (heuristic)	no

Also known as: intellectual disability, nonsyndromic, X-linked · intellectual disability, X-linked, nonsyndromic · isolated X-linked intellectual disability · mental retardation, nonsyndromic, X-linked · mental retardation, X-linked, nonsyndromic · non-specific X-linked intellectual disability · non-syndromic intellectual disability, X-linked · non-syndromic X-linked intellectual disability · nonsyndromic X-linked intellectual disability · X-linked non-specific intellectual disability · X-linked non-syndromic intellectual disability

Data availability: 21 ClinVar variants · 34 GenCC gene-disease records · 3 cell lines.

Disease family

An umbrella term covering 52 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › non-syndromic X-linked intellectual disability

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

21 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 likely pathogenic, 4 pathogenic, 2 conflicting classifications of pathogenicity, 1 not provided, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
143749	NM_001110792.2(MECP2):c.961C>T (p.Arg321Trp)	MECP2	Pathogenic	reviewed by expert panel
981982	NC_000023.10:g.(?153287263)(153363189_?)dup	MECP2	Pathogenic	criteria provided, single submitter
984750	GRCh37/hg19 Xp22.11(chrX:23395622-23463363)x0	PTCHD1	Pathogenic	no assertion criteria provided
156224	NM_016120.4(RLIM):c.1067A>G (p.Tyr356Cys)	RLIM	Pathogenic	criteria provided, single submitter
253088	NM_016120.4(RLIM):c.1159C>T (p.Arg387Cys)	RLIM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2661896	NM_001493.3(GDI1):c.671A>G (p.Tyr224Cys)	ATP6AP1	Likely pathogenic	criteria provided, single submitter
4849277	NM_173495.3(PTCHD1):c.317_325delinsCCTCCTTCCAGAA (p.Met106fs)	PTCHD1	Likely pathogenic	no assertion criteria provided
984894	NM_173495.3(PTCHD1):c.1985_1986del (p.Leu661_Tyr662insTer)	PTCHD1	Likely pathogenic	no assertion criteria provided
3250359	NM_001282874.2(SMARCA1):c.413T>G (p.Leu138Ter)	SMARCA1	Likely pathogenic	criteria provided, single submitter
3250360	NM_001282874.2(SMARCA1):c.193C>T (p.Gln65Ter)	SMARCA1	Likely pathogenic	criteria provided, single submitter
434072	NM_001318510.2(ACSL4):c.1698-10G>A	ACSL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
495142	NM_001318510.2(ACSL4):c.1391-7T>C	ACSL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1335795	NM_002025.4(AFF2):c.2082G>T (p.Lys694Asn)	AFF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779230	NM_002025.4(AFF2):c.2009G>T (p.Arg670Leu)	AFF2	Uncertain significance	criteria provided, single submitter
864438	NM_001830.4(CLCN4):c.2021T>C (p.Met674Thr)	CLCN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
194123	NM_031407.7(HUWE1):c.811A>G (p.Arg271Gly)	HUWE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4532182	NM_173495.3(PTCHD1):c.465C>G (p.His155Gln)	PTCHD1	Uncertain significance	criteria provided, single submitter
4819046	NM_173495.3(PTCHD1):c.2443G>A (p.Val815Met)	PTCHD1	Uncertain significance	criteria provided, single submitter
1992382	NM_007137.5(ZNF81):c.1897A>T (p.Thr633Ser)	ZNF81	Uncertain significance	criteria provided, single submitter
283886	NM_002025.4(AFF2):c.1858A>G (p.Thr620Ala)	AFF2	Likely benign	criteria provided, multiple submitters, no conflicts
1679100	GRCh37/hg19 Xp11.4(chrX:38486922-38615759)x2	TSPAN7	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 202 · Orphanet: 62 · 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
DLG3	Definitive	X-linked	intellectual disability, X-linked 90	4
FTSJ1	Definitive	X-linked	intellectual disability, X-linked 9	4
HCFC1	Definitive	X-linked	X-linked intellectual disability	8
IL1RAPL1	Definitive	X-linked	intellectual disability, X-linked 21	6
IQSEC2	Definitive	X-linked	intellectual disability, X-linked 1	8
MECP2	Definitive	X-linked	syndromic X-linked intellectual disability Lubs type	13
MPP3	Definitive	X-linked	intellectual disability, X-linked 90	4
PAK3	Definitive	X-linked	intellectual disability, X-linked 30	6
PTCHD1	Definitive	X-linked	autism, susceptibility to, X-linked 4	4
RAB39B	Definitive	X-linked	intellectual disability, X-linked 72	9
RLIM	Definitive	X-linked	non-syndromic X-linked intellectual disability	7
SYP	Definitive	X-linked	intellectual disability, X-linked 96	6
TSPAN7	Definitive	X-linked	intellectual disability, X-linked 58	4
UPF3B	Definitive	X-linked	syndromic X-linked intellectual disability 14	6
USP9X	Definitive	X-linked	intellectual disability, X-linked 99, syndromic, female-restricted	9
ZNF711	Definitive	X-linked	intellectual disability, X-linked 97	5
ACSL4	Strong	X-linked	intellectual disability, X-linked 63	6
CLCN4	Strong	X-linked	intellectual disability, X-linked 49	4
FRMPD4	Strong	X-linked	intellectual disability, X-linked 104	6
GDI1	Strong	X-linked	intellectual disability, X-linked 41	5
RPS6KA3	Strong	X-linked	intellectual disability, X-linked 19	9
SLC9A7	Strong	X-linked	intellectual developmental disorder, X-linked 108	6
USP27X	Strong	X-linked	intellectual disability, X-linked 105	5
AGTR2	Supportive	X-linked	non-syndromic X-linked intellectual disability	2
ALG13	Supportive	X-linked	non-syndromic X-linked intellectual disability	7
ARHGEF6	Supportive	X-linked	non-syndromic X-linked intellectual disability	8
DMD	Supportive	X-linked	non-syndromic X-linked intellectual disability	12
MID2	Supportive	X-linked	non-syndromic X-linked intellectual disability	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSPAN7	Orphanet:777	X-linked non-syndromic intellectual disability
ZNF81	Orphanet:777	X-linked non-syndromic intellectual disability
RLIM	Orphanet:528084	Non-specific syndromic intellectual disability
CLCN4	Orphanet:485350	CLCN4-related X-linked intellectual disability syndrome
CLCN4	Orphanet:777	X-linked non-syndromic intellectual disability
PTCHD1	Orphanet:777	X-linked non-syndromic intellectual disability
ACSL4	Orphanet:777	X-linked non-syndromic intellectual disability
ACSL4	Orphanet:86818	Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome
MECP2	Orphanet:1762	Proximal Xq28 duplication syndrome
MECP2	Orphanet:209370	MECP2-related severe neonatal encephalopathy
MECP2	Orphanet:3077	X-linked intellectual disability-psychosis-macroorchidism syndrome
MECP2	Orphanet:3095	Atypical Rett syndrome
MECP2	Orphanet:536	Systemic lupus erythematosus
MECP2	Orphanet:777	X-linked non-syndromic intellectual disability
MECP2	Orphanet:778	Rett syndrome
RPS6KA3	Orphanet:192	Coffin-Lowry syndrome
RPS6KA3	Orphanet:276630	Symptomatic form of Coffin-Lowry syndrome in female carriers
RPS6KA3	Orphanet:777	X-linked non-syndromic intellectual disability
SYP	Orphanet:777	X-linked non-syndromic intellectual disability
USP9X	Orphanet:480880	X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability
USP9X	Orphanet:777	X-linked non-syndromic intellectual disability
ZNF711	Orphanet:777	X-linked non-syndromic intellectual disability
FTSJ1	Orphanet:777	X-linked non-syndromic intellectual disability
USP27X	Orphanet:777	X-linked non-syndromic intellectual disability
RAB39B	Orphanet:2379	Early-onset parkinsonism-intellectual disability syndrome
RAB39B	Orphanet:777	X-linked non-syndromic intellectual disability
SLC9A7	Orphanet:777	X-linked non-syndromic intellectual disability
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
UPF3B	Orphanet:776	Lujan-Fryns syndrome
UPF3B	Orphanet:777	X-linked non-syndromic intellectual disability
FRMPD4	Orphanet:777	X-linked non-syndromic intellectual disability
DLG3	Orphanet:777	X-linked non-syndromic intellectual disability
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
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy
ALG13	Orphanet:324422	ALG13-CDG

Cohort genes → proteins

36 cohort genes, 36 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	36

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSPAN7	HGNC:11854	ENSG00000156298	P41732	Tetraspanin-7	gencc,clinvar
ZNF81	HGNC:13156	ENSG00000197779	P51508	Zinc finger protein 81	gencc,clinvar
RLIM	HGNC:13429	ENSG00000131263	Q9NVW2	E3 ubiquitin-protein ligase RLIM	gencc,clinvar
CLCN4	HGNC:2022	ENSG00000073464	P51793	H(+)/Cl(-) exchange transporter 4	gencc,clinvar
PTCHD1	HGNC:26392	ENSG00000165186	Q96NR3	Patched domain-containing protein 1	gencc,clinvar
ACSL4	HGNC:3571	ENSG00000068366	O60488	Long-chain-fatty-acid–CoA ligase 4	gencc,clinvar
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	gencc,clinvar
RPS6KA3	HGNC:10432	ENSG00000177189	P51812	Ribosomal protein S6 kinase alpha-3	gencc
SYP	HGNC:11506	ENSG00000102003	P08247	Synaptophysin	gencc
USP9X	HGNC:12632	ENSG00000124486	Q93008	Ubiquitin carboxyl-terminal hydrolase 9X	gencc
ZNF41	HGNC:13107	ENSG00000147124	P51814	Zinc finger protein 41	gencc
ZNF711	HGNC:13128	ENSG00000147180	Q9Y462	Zinc finger protein 711	gencc
FTSJ1	HGNC:13254	ENSG00000068438	Q9UET6	tRNA (cytidine(32)/guanosine(34)-2’-O)-methyltransferase	gencc
USP27X	HGNC:13486	ENSG00000273820	A6NNY8	Ubiquitin carboxyl-terminal hydrolase 27	gencc
RAB39B	HGNC:16499	ENSG00000155961	Q96DA2	Ras-related protein Rab-39B	gencc
SLC9A7	HGNC:17123	ENSG00000065923	Q96T83	Sodium/hydrogen exchanger 7	gencc
ARX	HGNC:18060	ENSG00000004848	Q96QS3	Homeobox protein ARX	gencc
CNKSR2	HGNC:19701	ENSG00000149970	Q8WXI2	Connector enhancer of kinase suppressor of ras 2	gencc
UPF3B	HGNC:20439	ENSG00000125351	Q9BZI7	Regulator of nonsense transcripts 3B	gencc
FRMPD4	HGNC:29007	ENSG00000169933	Q14CM0	FERM and PDZ domain-containing protein 4	gencc
DLG3	HGNC:2902	ENSG00000082458	Q92796	Disks large homolog 3	gencc
IQSEC2	HGNC:29059	ENSG00000124313	Q5JU85	IQ motif and SEC7 domain-containing protein 2	gencc
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	gencc
ALG13	HGNC:30881	ENSG00000101901	Q9NP73	UDP-N-acetylglucosamine transferase subunit ALG13	gencc
AGTR2	HGNC:338	ENSG00000180772	P50052	Type-2 angiotensin II receptor	gencc
GDI1	HGNC:4226	ENSG00000203879	P31150	Rab GDP dissociation inhibitor alpha	gencc
HCFC1	HGNC:4839	ENSG00000172534	P51610	Host cell factor 1	gencc
IL1RAPL1	HGNC:5996	ENSG00000169306	Q9NZN1	Interleukin-1 receptor accessory protein-like 1	gencc
ARHGEF6	HGNC:685	ENSG00000129675	Q15052	Rho guanine nucleotide exchange factor 6	gencc
MID2	HGNC:7096	ENSG00000080561	Q9UJV3	Probable E3 ubiquitin-protein ligase MID2	gencc
MPP3	HGNC:7221	ENSG00000161647	Q13368	MAGUK p55 subfamily member 3	gencc
PAK3	HGNC:8592	ENSG00000077264	O75914	Serine/threonine-protein kinase PAK 3	gencc
SMARCA1	HGNC:11097	ENSG00000102038	P28370	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 1	clinvar
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	clinvar
AFF2	HGNC:3776	ENSG00000155966	P51816	AF4/FMR2 family member 2	clinvar
ATP6AP1	HGNC:868	ENSG00000071553	Q15904	V-type proton ATPase subunit S1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSPAN7	Tetraspanin-7	May be involved in cell proliferation and cell motility.
ZNF81	Zinc finger protein 81	May be involved in transcriptional regulation.
RLIM	E3 ubiquitin-protein ligase RLIM	E3 ubiquitin-protein ligase that acts as a negative coregulator for LIM homeodomain transcription factors by mediating the ubiquitination and subsequent degradation of LIM cofactors LDB1 and LDB2 and by mediating the recruitment the SIN3a/…
CLCN4	H(+)/Cl(-) exchange transporter 4	Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.
PTCHD1	Patched domain-containing protein 1	Required for the development and function of the thalamic reticular nucleus (TRN), a part of the thalamus that is critical for thalamocortical transmission, generation of sleep rhythms, sensorimotor processing and attention.
ACSL4	Long-chain-fatty-acid–CoA ligase 4	Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation.
MECP2	Methyl-CpG-binding protein 2	Chromosomal protein that binds to methylated DNA.
RPS6KA3	Ribosomal protein S6 kinase alpha-3	Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation thr…
SYP	Synaptophysin	Possibly involved in structural functions as organizing other membrane components or in targeting the vesicles to the plasma membrane.
USP9X	Ubiquitin carboxyl-terminal hydrolase 9X	Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins.
ZNF41	Zinc finger protein 41	May be involved in transcriptional regulation.
ZNF711	Zinc finger protein 711	Transcription regulator required for brain development.
FTSJ1	tRNA (cytidine(32)/guanosine(34)-2’-O)-methyltransferase	Methylates the 2’-O-ribose of nucleotides at positions 32 and 34 of the tRNA anticodon loop of substrate tRNAs.
USP27X	Ubiquitin carboxyl-terminal hydrolase 27	Deubiquitinase involved in innate antiviral immunity by mediating deubiquitination of CGAS and RIGI.
RAB39B	Ras-related protein Rab-39B	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
SLC9A7	Sodium/hydrogen exchanger 7	Golgi Na(+), K(+)/(H+) antiporter.
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.
UPF3B	Regulator of nonsense transcripts 3B	Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery.
FRMPD4	FERM and PDZ domain-containing protein 4	Positive regulator of dendritic spine morphogenesis and density.
DLG3	Disks large homolog 3	Required for learning most likely through its role in synaptic plasticity following NMDA receptor signaling.
IQSEC2	IQ motif and SEC7 domain-containing protein 2	Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins.
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
ALG13	UDP-N-acetylglucosamine transferase subunit ALG13	Catalytic subunit of the UDP-N-acetylglucosamine transferase complex that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
AGTR2	Type-2 angiotensin II receptor	Receptor for angiotensin II, a vasoconstricting peptide.
GDI1	Rab GDP dissociation inhibitor alpha	Regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them.
HCFC1	Host cell factor 1	Transcriptional coregulator.
IL1RAPL1	Interleukin-1 receptor accessory protein-like 1	May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel.
ARHGEF6	Rho guanine nucleotide exchange factor 6	Acts as a RAC1 guanine nucleotide exchange factor (GEF).
MID2	Probable E3 ubiquitin-protein ligase MID2	E3 ubiquitin ligase that plays a role in microtubule stabilization.
MPP3	MAGUK p55 subfamily member 3	Participates in cell spreading through the phosphoinositide-3-kinase (PI3K) pathway by connecting CADM1 to DLG1 and the regulatory subunit of phosphoinositide-3-kinase (PI3K).
PAK3	Serine/threonine-protein kinase PAK 3	Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation.
SMARCA1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 1	ATPase that possesses intrinsic ATP-dependent chromatin-remodeling activity.
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.
AFF2	AF4/FMR2 family member 2	RNA-binding protein.
ATP6AP1	V-type proton ATPase subunit S1	Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles.

Protein-family classification

Druggable: 11 · Difficult: 12 · Unknown: 13 · Druggable fraction: 0.31

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	4	3.1×	0.250
Transcription factor	8	1.8×	0.250
Scaffold/PPI	4	1.9×	0.407
Protease	2	2.0×	0.516
Antibody/Immunoglobulin	2	1.6×	0.561
Enzyme (other)	2	0.7×	0.931
GPCR	1	0.7×	0.931
Other/Unknown	13	0.7×	0.995

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSPAN7	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
ZNF81	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
RLIM	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, RING_finger_E3_ligase
CLCN4	Other/Unknown	no		CBS_dom, ClC, Cl_channel-4
PTCHD1	Other/Unknown	no		SSD, PTHD_SSD, Patched_domain-protein
ACSL4	Enzyme (other)	yes	6.2.1.15	AMP-dep_synth/lig_dom, AMP-binding_CS, ANL_N_sf
MECP2	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA-bd_dom_sf, Me_CpG-bd_MeCP2
RPS6KA3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
SYP	Other/Unknown	no		Synaptophysin/porin, Marvel
USP9X	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS
ZNF41	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
ZNF711	Transcription factor	no		Transcrp_activ_Zfx/Zfy-dom, Znf_C2H2_type, Znf_C2H2_sf
FTSJ1	Other/Unknown	no		RNA_MeTrfase_FtsJ_dom, rRNA-MeTfrase_E, RNA_methyltr_E_TRM7
USP27X	Protease	yes		Peptidase_C19_UCH, USP_CS, USP
RAB39B	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
SLC9A7	Other/Unknown	no		NHE-6/7/9, NaH_exchanger, Cation/H_exchanger_TM
ARX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
CNKSR2	Scaffold/PPI	no		PDZ, SAM, PH_domain
UPF3B	Other/Unknown	no		UPF3_dom, Nucleotide-bd_a/b_plait_sf, UPF3B_RRM-like
FRMPD4	Scaffold/PPI	no		FERM_domain, WW_dom, PDZ
DLG3	Kinase	yes		SH3_domain, PDZ, Guanylate_kin-like_dom
IQSEC2	Scaffold/PPI	no		Sec7_dom, PH_domain, PH-like_dom_sf
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
ALG13	Other/Unknown	no		Tudor, OTU_dom, Glyco_trans_28_C
AGTR2	GPCR	yes		ATII_AT2_rcpt, ATII_rcpt, GPCR_Rhodpsn
GDI1	Other/Unknown	no		RabGDI, GDP_dissociation_inhibitor, FAD/NAD-bd_sf
HCFC1	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Kelch-typ_b-propeller
IL1RAPL1	Antibody/Immunoglobulin	yes		TIR_dom, Ig_sub2, Ig_sub
ARHGEF6	Scaffold/PPI	no		DH_dom, SH3_domain, CH_dom
MID2	Transcription factor	no		Znf_B-box, Znf_RING, B30.2/SPRY
MPP3	Kinase	yes		SH3_domain, PDZ, L27_dom
PAK3	Kinase	yes	2.7.11.1	CRIB_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
SMARCA1	Transcription factor	no		SNF2_N, SANT/Myb, Helicase_C-like
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_sf
AFF2	Other/Unknown	no		AF4/FMR2, AF4_int, AF4/FMR2_CHD
ATP6AP1	Other/Unknown	no		Ac45_acc_su, VAS1_LD, VAS1/VOA1_TM

Expression context

Cohort genes with no expression data: 0.

30 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)	36
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	6
adrenal tissue	5
middle temporal gyrus	5
Brodmann (1909) area 23	5
cerebellar hemisphere	5
buccal mucosa cell	4
cerebellar cortex	4
cortical plate	4
cartilage tissue	3
right hemisphere of cerebellum	3
primordial germ cell in gonad	2
Brodmann (1909) area 10	2
paraflocculus	2
sural nerve	2
endometrium epithelium	2
ganglionic eminence	2
skeletal muscle tissue of rectus abdominis	2
calcaneal tendon	2
caudate nucleus	1
dorsolateral prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSPAN7	281	broad	marker	caudate nucleus, nucleus accumbens, dorsolateral prefrontal cortex
ZNF81	249	ubiquitous	yes	colonic epithelium, primordial germ cell in gonad, germinal epithelium of ovary
RLIM	256	ubiquitous	marker	middle temporal gyrus, cartilage tissue, adrenal tissue
CLCN4	247	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, postcentral gyrus
PTCHD1	167	broad	yes	cauda epididymis, corpus epididymis, buccal mucosa cell
ACSL4	268	ubiquitous	marker	adrenal tissue, monocyte, mononuclear cell
MECP2	277	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, sural nerve
RPS6KA3	285	ubiquitous	marker	cartilage tissue, mucosa of sigmoid colon, colonic mucosa
SYP	206	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
USP9X	295	ubiquitous	marker	middle frontal gyrus, endometrium epithelium, secondary oocyte
ZNF41	179	ubiquitous	yes	muscle of leg, primordial germ cell in gonad, gastrocnemius
ZNF711	241	broad	marker	endothelial cell, cortical plate, ganglionic eminence
FTSJ1	292	ubiquitous	marker	stromal cell of endometrium, granulocyte, cortical plate
USP27X	236	ubiquitous	yes	buccal mucosa cell, endothelial cell, cerebellar vermis
RAB39B	172	broad	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
SLC9A7	248	ubiquitous	marker	pons, lateral globus pallidus, superior vestibular nucleus
ARX	162	broad	marker	left ovary, ovary, right ovary
CNKSR2	226	broad	marker	Brodmann (1909) area 23, cerebellar cortex, cerebellar hemisphere
UPF3B	277	ubiquitous	marker	sural nerve, esophagus squamous epithelium, embryo
FRMPD4	117	broad	marker	middle temporal gyrus, endothelial cell, Brodmann (1909) area 23
DLG3	276	ubiquitous	marker	cortical plate, body of pancreas, buccal mucosa cell
IQSEC2	236	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
ALG13	287	ubiquitous	marker	calcaneal tendon, adrenal tissue, right uterine tube
AGTR2	77	tissue_specific	marker	adrenal tissue, ileal mucosa, smooth muscle tissue
GDI1	294	ubiquitous	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
HCFC1	274	ubiquitous	marker	tendon of biceps brachii, parotid gland, skeletal muscle tissue of rectus abdominis
IL1RAPL1	115	broad	marker	buccal mucosa cell, endothelial cell, corpus callosum
ARHGEF6	289	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, medial globus pallidus
MID2	258	ubiquitous	marker	tibialis anterior, islet of Langerhans, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 22.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HUWE1	5,793
MECP2	5,688
SMARCA1	4,447
DLG3	3,967
SYP	3,655
USP9X	3,484
ACSL4	3,040
FTSJ1	2,850
RPS6KA3	2,713
HCFC1	2,637

Intra-cohort edges

A	B	Sources
AFF2	GDI1	string_interaction
AFF2	IL1RAPL1	string_interaction
ARHGEF6	CNKSR2	string_interaction
ARHGEF6	PAK3	string_interaction
ARHGEF6	TSPAN7	string_interaction
ARHGEF6	ZNF41	string_interaction
ARHGEF6	ZNF81	string_interaction
ATP6AP1	GDI1	string_interaction
CNKSR2	DLG3	intact
CNKSR2	FRMPD4	string_interaction
DLG3	FRMPD4	intact, string_interaction
DLG3	IQSEC2	intact
FRMPD4	MPP3	intact, string_interaction
FTSJ1	ZNF41	string_interaction
GDI1	MECP2	string_interaction
GDI1	RAB39B	string_interaction
GDI1	TSPAN7	string_interaction
HUWE1	USP9X	intact, string_interaction
IL1RAPL1	TSPAN7	string_interaction
MECP2	PTCHD1	string_interaction
RLIM	UPF3B	biogrid_interaction, intact
RPS6KA3	USP9X	intact

Structural data

PDB: 21 · AlphaFold-only: 15 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HUWE1	Q7Z6Z7	19
RPS6KA3	P51812	15
HCFC1	P51610	11
MECP2	P51608	9
ATP6AP1	Q15904	9
AGTR2	P50052	7
DMD	P11532	6
FRMPD4	Q14CM0	5
USP9X	Q93008	4
MID2	Q9UJV3	4
RLIM	Q9NVW2	3
UPF3B	Q9BZI7	3
DLG3	Q92796	3
IL1RAPL1	Q9NZN1	3
CNKSR2	Q8WXI2	2
IQSEC2	Q5JU85	2
ARHGEF6	Q15052	2
ZNF711	Q9Y462	1
FTSJ1	Q9UET6	1
RAB39B	Q96DA2	1
PAK3	O75914	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GDI1	P31150	93.32
ACSL4	O60488	90.46
TSPAN7	P41732	89.18
CLCN4	P51793	84.66
PTCHD1	Q96NR3	84.14
MPP3	Q13368	78.54
USP27X	A6NNY8	78.52
SYP	P08247	77.92
SMARCA1	P28370	75.48
SLC9A7	Q96T83	67.55
ZNF41	P51814	64.52
ZNF81	P51508	63.12
ARX	Q96QS3	56.51
ALG13	Q9NP73	54.42
AFF2	P51816	49.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 171. Enrichment computed across 36 evidence-associated genes (26 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 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHOU GTPase cycle	3	32.1×	0.018	USP9X, ARHGEF6, PAK3
Loss of MECP2 binding ability to 5hmC-DNA	1	439.2×	0.172	MECP2
Defective ALG14 causes ALG14-CMS	1	219.6×	0.172	ALG13
Free fatty acids regulate insulin secretion	1	146.4×	0.172	ACSL4
Intracellular metabolism of fatty acids regulates insulin secretion	1	146.4×	0.172	ACSL4
MECP2 regulates transcription of genes involved in GABA signaling	1	146.4×	0.172	MECP2
Interleukin-38 signaling	1	109.8×	0.172	IL1RAPL1
Loss of phosphorylation of MECP2 at T308	1	109.8×	0.172	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	109.8×	0.172	MECP2
MECP2 regulates transcription factors	1	87.8×	0.175	MECP2
G-protein beta:gamma signalling	1	73.2×	0.175	ARHGEF6
CREB phosphorylation	1	62.8×	0.175	RPS6KA3
NrCAM interactions	1	62.8×	0.175	DLG3
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	62.8×	0.175	MECP2
RSK activation	1	54.9×	0.175	RPS6KA3
Regulation of cytoskeletal remodeling and cell spreading by IPP complex components	1	54.9×	0.175	ARHGEF6
MECP2 regulates transcription of neuronal ligands	1	54.9×	0.175	MECP2
RAB GEFs exchange GTP for GDP on RABs	2	9.6×	0.175	RAB39B, GDI1
Sodium/Proton exchangers	1	48.8×	0.182	SLC9A7
GPCR downstream signalling	3	5.0×	0.182	RPS6KA3, AGTR2, ARHGEF6
Activation of Ca-permeable Kainate Receptor	1	43.9×	0.184	DLG3
CD28 dependent Vav1 pathway	1	33.8×	0.195	PAK3
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	33.8×	0.195	RPS6KA3
Gastrin-CREB signalling pathway via PKC and MAPK	1	33.8×	0.195	RPS6KA3
Activation of RAC1	1	31.4×	0.195	PAK3
ERK/MAPK targets	1	25.8×	0.195	RPS6KA3
Sema3A PAK dependent Axon repulsion	1	25.8×	0.195	PAK3
Trafficking of GluR2-containing AMPA receptors	1	25.8×	0.195	TSPAN7
Cell-extracellular matrix interactions	1	25.8×	0.195	ARHGEF6
Diseases associated with N-glycosylation of proteins	1	24.4×	0.195	ALG13

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 34 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of systemic arterial blood pressure by circulatory renin-angiotensin	1	495.6×	0.047	AGTR2
negative regulation of prostaglandin secretion	1	495.6×	0.047	ACSL4
catecholamine secretion	1	495.6×	0.047	MECP2
regulation of muscle system process	1	495.6×	0.047	DMD
regulation of cellular response to growth factor stimulus	1	495.6×	0.047	DMD
trans-synaptic signaling by BDNF	1	495.6×	0.047	MECP2
brain renin-angiotensin system	1	247.8×	0.047	AGTR2
tRNA nucleoside ribose methylation	1	247.8×	0.047	FTSJ1
wobble position ribose methylation	1	247.8×	0.047	FTSJ1
G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger	1	247.8×	0.047	AGTR2
embryonic olfactory bulb interneuron precursor migration	1	247.8×	0.047	ARX
cardiolipin metabolic process	1	247.8×	0.047	MECP2
regulation of metanephros size	1	247.8×	0.047	AGTR2
cardiac muscle cell action potential	1	247.8×	0.047	DMD
obsolete regulation of Golgi lumen acidification	1	247.8×	0.047	SLC9A7
nervous system process involved in regulation of systemic arterial blood pressure	1	165.2×	0.047	MECP2
angiotensin-mediated vasodilation involved in regulation of systemic arterial blood pressure	1	165.2×	0.047	AGTR2
biogenic amine metabolic process	1	165.2×	0.047	MECP2
release from viral latency	1	165.2×	0.047	HCFC1
regulation of translation in response to stress	1	165.2×	0.047	RPS6KA3
response to other organism	1	165.2×	0.047	MECP2
positive regulation of synapse structural plasticity	1	165.2×	0.047	FRMPD4
positive regulation of metanephric glomerulus development	1	165.2×	0.047	AGTR2
inhibitory chemical synaptic transmission	1	165.2×	0.047	PTCHD1
postsynaptic specialization organization	1	165.2×	0.047	CNKSR2
trans-synaptic signaling by trans-synaptic complex	1	165.2×	0.047	IL1RAPL1
negative regulation of protein localization	1	165.2×	0.047	GDI1
regulation of opioid receptor signaling pathway	1	165.2×	0.047	SYP
regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion	1	123.9×	0.047	DMD
proprioception	1	123.9×	0.047	MECP2

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 6 · Undrugged: 30

Druggability breadth: 16 of 36 evidence-associated genes (44%) 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
RPS6KA3	FEDRATINIB
AGTR2	IRBESARTAN
PAK3	BOSUTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPS6KA3	46	4
AGTR2	19	4
PAK3	17	4
USP9X	1	2
HCFC1	1	2
AFF2	1	2
TSPAN7	0	0
ZNF81	0	0
RLIM	0	0
CLCN4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	RPS6KA3
PALBOCICLIB	4	RPS6KA3
ENTRECTINIB	4	RPS6KA3
BOSUTINIB	4	PAK3, RPS6KA3
GILTERITINIB	4	RPS6KA3
BRIGATINIB	4	RPS6KA3
UPADACITINIB	4	RPS6KA3
NINTEDANIB	4	PAK3, RPS6KA3
SUNITINIB	4	PAK3, RPS6KA3
QUIZARTINIB	4	PAK3, RPS6KA3
MIDOSTAURIN	4	PAK3, RPS6KA3
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
ENZASTAURIN	3	PAK3, RPS6KA3
FASUDIL	3	RPS6KA3
ALVOCIDIB	3	RPS6KA3
ALISERTIB	3	RPS6KA3
DOVITINIB	3	PAK3, RPS6KA3
LESTAURTINIB	3	PAK3, RPS6KA3
RUBOXISTAURIN	3	RPS6KA3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
RPS6KA3	770	Binding:768, Functional:1, ADMET:1
AGTR2	244	Binding:188, Functional:56
PAK3	240	Binding:240
USP9X	41	Binding:41
HCFC1	8	Binding:8
AFF2	8	Binding:8
ATP6AP1	7	Binding:7
ARHGEF6	6	Binding:6
HUWE1	4	Binding:3, Functional:1
USP27X	3	Binding:3
ACSL4	2	Binding:2
MECP2	1	Binding:1
CNKSR2	1	Binding:1
GDI1	1	Binding:1
SMARCA1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACSL4	6.2.1.15, 6.2.1.3	arachidonate-CoA ligase, long-chain-fatty-acid-CoA ligase
RPS6KA3	2.7.11.1	non-specific serine/threonine protein kinase
PAK3	2.7.11.1	non-specific serine/threonine protein kinase
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RPS6KA3	770
AGTR2	244
PAK3	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 36; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
FEDRATINIB	4	RPS6KA3
PALBOCICLIB	4	RPS6KA3
ENTRECTINIB	4	RPS6KA3
BOSUTINIB	4	PAK3, RPS6KA3
GILTERITINIB	4	RPS6KA3
BRIGATINIB	4	RPS6KA3
UPADACITINIB	4	RPS6KA3
NINTEDANIB	4	PAK3, RPS6KA3
SUNITINIB	4	PAK3, RPS6KA3
QUIZARTINIB	4	PAK3, RPS6KA3
MIDOSTAURIN	4	PAK3, RPS6KA3
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
ENZASTAURIN	3	PAK3, RPS6KA3
FASUDIL	3	RPS6KA3
ALVOCIDIB	3	RPS6KA3
ALISERTIB	3	RPS6KA3
DOVITINIB	3	PAK3, RPS6KA3
LESTAURTINIB	3	PAK3, RPS6KA3
RUBOXISTAURIN	3	RPS6KA3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	RPS6KA3, AGTR2, PAK3
B	Phased (≥1) drug, not yet approved	3	USP9X, HCFC1, AFF2
C	Druggable family + PDB, no drug	3	DLG3, IL1RAPL1, HUWE1
D	Druggable family + AlphaFold only, no drug	3	ACSL4, USP27X, MPP3
E	Difficult family or no structure, no drug	24	TSPAN7, ZNF81, RLIM, CLCN4, PTCHD1, MECP2, SYP, ZNF41, ZNF711, FTSJ1 (+14 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TSPAN7	0	—
ZNF81	0	—
RLIM	0	—
CLCN4	0	—
PTCHD1	0	—
ACSL4	2	—
MECP2	1	—
SYP	0	—
ZNF41	0	—
ZNF711	0	—
FTSJ1	0	—
USP27X	3	—
RAB39B	0	—
SLC9A7	0	—
ARX	0	—
CNKSR2	1	—
UPF3B	0	—
FRMPD4	0	—
DLG3	0	—
IQSEC2	0	—
DMD	0	—
ALG13	0	—
GDI1	1	—
IL1RAPL1	0	—
ARHGEF6	6	—
MID2	0	—
MPP3	0	—
SMARCA1	1	—
HUWE1	4	—
ATP6AP1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: TSPAN7, ZNF81, RLIM, CLCN4, PTCHD1, ACSL4, MECP2, RPS6KA3, SYP, USP9X, ZNF41, ZNF711, FTSJ1, USP27X, RAB39B, SLC9A7, ARX, CNKSR2, UPF3B, FRMPD4, DLG3, IQSEC2, DMD, ALG13, AGTR2, GDI1, HCFC1, IL1RAPL1, ARHGEF6, MID2, MPP3, PAK3, SMARCA1, HUWE1, AFF2, ATP6AP1