Intellectual disability, autosomal dominant 48

Summary

Intellectual disability, autosomal dominant 48 (MONDO:0030913) is a disease caused by RAC1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RAC1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 36
• Phenotypes (HPO): 50

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000733	Abnormal repetitive mannerisms	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000363	Abnormality of earlobe	Occasional (5-29%)
HP:0000403	Recurrent otitis media	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001647	Bicuspid aortic valve	Occasional (5-29%)
HP:0001655	Patent foramen ovale	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0002280	Enlarged cisterna magna	Occasional (5-29%)
HP:0002365	Hypoplasia of the brainstem	Occasional (5-29%)
HP:0002518	Abnormal periventricular white matter morphology	Occasional (5-29%)
HP:0002553	Highly arched eyebrow	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002786	Tracheobronchomalacia	Occasional (5-29%)
HP:0003086	Acromesomelia	Occasional (5-29%)
HP:0006532	Recurrent pneumonia	Occasional (5-29%)
HP:0007033	Cerebellar dysplasia	Occasional (5-29%)
HP:0008527	Congenital sensorineural hearing impairment	Occasional (5-29%)
HP:0009237	Short 5th finger	Occasional (5-29%)
HP:0009765	Low hanging columella	Occasional (5-29%)
HP:0030515	Moderately reduced visual acuity	Occasional (5-29%)
HP:0200007	Abnormal size of the palpebral fissures	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 48
Mondo ID	MONDO:0030913
OMIM	617751
Orphanet	500159
DOID	DOID:0080235
UMLS	C4540321
MedGen	1619532
GARD	0017924
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 48 · intellectual disability, autosomal dominant 48 · mental retardation, autosomal dominant 48 · MRD48

Data availability: 36 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › intellectual disability, autosomal dominant 48

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

36 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 8 likely pathogenic, 8 pathogenic, 7 pathogenic/likely pathogenic, 2 benign, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1098331	NM_006908.5(RAC1):c.218C>T (p.Pro73Leu)	RAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685419	NM_006908.5(RAC1):c.212C>T (p.Ser71Phe)	RAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1727258	NM_006908.5(RAC1):c.475G>A (p.Ala159Thr)	RAC1	Pathogenic	criteria provided, single submitter
1727259	NM_006908.5(RAC1):c.184G>A (p.Glu62Lys)	RAC1	Pathogenic	criteria provided, single submitter
2446363	NM_006908.5(RAC1):c.181C>G (p.Gln61Glu)	RAC1	Pathogenic	criteria provided, single submitter
2446365	NM_006908.5(RAC1):c.202C>A (p.Arg68Ser)	RAC1	Pathogenic	no assertion criteria provided
2446366	NM_006908.5(RAC1):c.202C>G (p.Arg68Gly)	RAC1	Pathogenic	no assertion criteria provided
3377146	NM_006908.5(RAC1):c.94T>C (p.Tyr32His)	RAC1	Pathogenic	criteria provided, single submitter
445280	NM_006908.5(RAC1):c.53G>A (p.Cys18Tyr)	RAC1	Pathogenic	criteria provided, single submitter
445281	NM_006908.5(RAC1):c.116A>G (p.Asn39Ser)	RAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
445283	NM_006908.5(RAC1):c.190T>G (p.Tyr64Asp)	RAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
445284	NM_006908.5(RAC1):c.151G>A (p.Val51Met)	RAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
625787	GRCh37/hg19 7p22.1(chr7:6385256-6431775)	RAC1	Pathogenic	criteria provided, single submitter
218339	NM_000965.5(RARB):c.638T>C (p.Leu213Pro)	RARB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88762	NM_000965.5(RARB):c.1159C>T (p.Arg387Cys)	RARB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027690	NM_006908.5(RAC1):c.168G>C (p.Trp56Cys)	RAC1	Likely pathogenic	criteria provided, single submitter
1333690	NM_006908.5(RAC1):c.191A>G (p.Tyr64Cys)	RAC1	Likely pathogenic	criteria provided, single submitter
2431922	NM_006908.5(RAC1):c.190T>C (p.Tyr64His)	RAC1	Likely pathogenic	criteria provided, single submitter
3235757	NM_006908.5(RAC1):c.129T>A (p.Asn43Lys)	RAC1	Likely pathogenic	criteria provided, single submitter
4082372	NM_006908.5(RAC1):c.178G>A (p.Gly60Arg)	RAC1	Likely pathogenic	criteria provided, single submitter
445282	NM_006908.5(RAC1):c.470G>A (p.Cys157Tyr)	RAC1	Likely pathogenic	criteria provided, single submitter
445285	NM_006908.5(RAC1):c.151G>C (p.Val51Leu)	RAC1	Likely pathogenic	criteria provided, single submitter
4532075	NM_006908.5(RAC1):c.171T>G (p.Asp57Glu)	RAC1	Likely pathogenic	criteria provided, single submitter
974895	NM_006908.5(RAC1):c.198A>T (p.Arg66Ser)	RAC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033910	NM_006908.5(RAC1):c.372C>G (p.Asp124Glu)	RAC1	Uncertain significance	criteria provided, single submitter
1699147	NM_006908.5(RAC1):c.409A>G (p.Ile137Val)	RAC1	Uncertain significance	criteria provided, single submitter
2435353	NM_006908.5(RAC1):c.170A>C (p.Asp57Ala)	RAC1	Uncertain significance	criteria provided, single submitter
2435354	NM_006908.5(RAC1):c.478C>G (p.Leu160Val)	RAC1	Uncertain significance	criteria provided, single submitter
2689856	NM_006908.5(RAC1):c.280C>T (p.Arg94Cys)	RAC1	Uncertain significance	criteria provided, single submitter
3377155	NM_006908.5(RAC1):c.176C>G (p.Ala59Gly)	RAC1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
RAC1	Strong	Autosomal dominant	intellectual disability, autosomal dominant 48	5
RNASE1	Strong	Autosomal dominant	intellectual disability, autosomal dominant 48	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAC1	Orphanet:500159	Microcephaly-corpus callosum and cerebellar vermis hypoplasia-facial dysmorphism-intellectual disability syndrom
RARB	Orphanet:689829	Microphthalmia-motor delay-language delay-brain anomalies-diaphragmatic hernia syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNASE1	HGNC:10044	ENSG00000129538	P07998	Ribonuclease pancreatic	gencc,clinvar
RAC1	HGNC:9801	ENSG00000136238	P63000	Ras-related C3 botulinum toxin substrate 1	gencc,clinvar
RARB	HGNC:9865	ENSG00000077092	P10826	Retinoic acid receptor beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNASE1	Ribonuclease pancreatic	Endonuclease that catalyzes the cleavage of RNA on the 3’ side of pyrimidine nucleotides.
RAC1	Ras-related C3 botulinum toxin substrate 1	Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states.
RARB	Retinoic acid receptor beta	Receptor for retinoic acid.

Protein-family classification

Druggable: 3 · 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
Nuclear receptor	1	128.6×	0.016
Enzyme (other)	2	8.0×	0.020

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASE1	Enzyme (other)	yes	4.6.1.18	RNaseA, RNaseA_AS, RNaseA_domain
RAC1	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTPase_Rho, Small_GTP-bd
RARB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right lung	1
right testis	1
epithelium of esophagus	1
esophagus squamous epithelium	1
visceral pleura	1
buccal mucosa cell	1
choroid plexus epithelium	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASE1	283	broad	marker	left testis, right testis, right lung
RAC1	295	ubiquitous	marker	esophagus squamous epithelium, epithelium of esophagus, visceral pleura
RARB	210	ubiquitous	marker	choroid plexus epithelium, palpebral conjunctiva, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RARB	2,185
RAC1	2,182
RNASE1	1,266

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAC1	P63000	79
RNASE1	P07998	12
RARB	P10826	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 56. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NTRK2 activates RAC1	1	634.4×	0.015	RAC1
Activated NTRK2 signals through CDK5	1	634.4×	0.015	RAC1
Sema4D mediated inhibition of cell attachment and migration	1	475.8×	0.015	RAC1
Inactivation of CDC42 and RAC1	1	475.8×	0.015	RAC1
Activation of RAC1 downstream of NMDARs	1	475.8×	0.015	RAC1
Nef and signal transduction	1	423.0×	0.015	RAC1
RHO GTPases activate KTN1	1	346.1×	0.015	RAC1
MET activates RAP1 and RAC1	1	346.1×	0.015	RAC1
WNT5:FZD7-mediated leishmania damping	1	317.2×	0.015	RAC1
CD28 dependent Vav1 pathway	1	292.8×	0.015	RAC1
Activation of RAC1	1	271.9×	0.015	RAC1
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	271.9×	0.015	RAC1
SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion	1	253.8×	0.015	RAC1
DCC mediated attractive signaling	1	237.9×	0.015	RAC1
Sema3A PAK dependent Axon repulsion	1	223.9×	0.015	RAC1
RHO GTPases activate CIT	1	200.3×	0.015	RAC1
Ephrin signaling	1	190.3×	0.015	RAC1
RHO GTPases activate PAKs	1	181.3×	0.015	RAC1
Signal transduction by L1	1	173.0×	0.015	RAC1
Chaperone Mediated Autophagy	1	165.5×	0.015	RNASE1
Azathioprine ADME	1	165.5×	0.015	RAC1
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	165.5×	0.015	RAC1
RHO GTPases Activate NADPH Oxidases	1	152.3×	0.016	RAC1
VEGFR2 mediated vascular permeability	1	135.9×	0.016	RAC1
Signaling by Retinoic Acid	1	135.9×	0.016	RARB
DAP12 signaling	1	122.8×	0.016	RAC1
FCERI mediated MAPK activation	1	115.3×	0.016	RAC1
RHO GTPases activate IQGAPs	1	115.3×	0.016	RAC1
Late endosomal microautophagy	1	108.8×	0.016	RNASE1
RHO GTPases activate PKNs	1	105.7×	0.016	RAC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
anatomical structure arrangement	1	5617.3×	0.006	RAC1
embryonic olfactory bulb interneuron precursor migration	1	2808.7×	0.006	RAC1
cerebral cortex GABAergic interneuron development	1	2808.7×	0.006	RAC1
negative regulation of interleukin-23 production	1	2808.7×	0.006	RAC1
regulation of ERK5 cascade	1	2808.7×	0.006	RAC1
angiotensin-activated signaling pathway involved in heart process	1	2808.7×	0.006	RAC1
positive regulation of ovarian follicle development	1	2808.7×	0.006	RAC1
regulation of neuron maturation	1	1872.4×	0.006	RAC1
localization within membrane	1	1872.4×	0.006	RAC1
regulation of cell adhesion involved in heart morphogenesis	1	1872.4×	0.006	RAC1
auditory receptor cell morphogenesis	1	1404.3×	0.006	RAC1
regulation of respiratory burst	1	1404.3×	0.006	RAC1
regulation of neutrophil migration	1	1404.3×	0.006	RAC1
glandular epithelial cell development	1	1123.5×	0.007	RARB
erythrocyte enucleation	1	1123.5×	0.007	RAC1
regulation of hydrogen peroxide metabolic process	1	936.2×	0.007	RAC1
ventricular cardiac muscle cell differentiation	1	802.5×	0.007	RARB
growth plate cartilage development	1	702.2×	0.007	RARB
hepatocyte growth factor receptor signaling pathway	1	702.2×	0.007	RAC1
regulation of lamellipodium assembly	1	624.1×	0.007	RAC1
engulfment of apoptotic cell	1	624.1×	0.007	RAC1
negative regulation of receptor-mediated endocytosis	1	624.1×	0.007	RAC1
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	624.1×	0.007	RAC1
sphingosine-1-phosphate receptor signaling pathway	1	561.7×	0.007	RAC1
hyperosmotic response	1	561.7×	0.007	RAC1
cerebral cortex radially oriented cell migration	1	561.7×	0.007	RAC1
cortical cytoskeleton organization	1	561.7×	0.007	RAC1
regulation of nitric oxide biosynthetic process	1	561.7×	0.007	RAC1
positive regulation of bicellular tight junction assembly	1	561.7×	0.007	RAC1
negative regulation of fibroblast migration	1	510.7×	0.007	RAC1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
RAC1	KETOROLAC
RARB	BEXAROTENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RARB	18	4
RAC1	3	4
RNASE1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KETOROLAC	4	RAC1
BEXAROTENE	4	RARB
AMOXICILLIN	4	RARB
ADAPALENE	4	RARB
TOLCAPONE	4	RARB
KETOCONAZOLE	4	RARB
CYCLOSPORINE	4	RARB
TAZAROTENE	4	RARB
TAMIBAROTENE	4	RARB
TRIFAROTENE	4	RARB
TRETINOIN	4	RARB
TROGLITAZONE	4	RARB
TROVAFLOXACIN	4	RARB
ALPROSTADIL	4	RARB
IBUPROFEN	4	RARB
ZAFIRLUKAST	4	RARB
ALITRETINOIN	4	RARB
SANGUINARIUM CHLORIDE	2	RAC1
CONESSINE	2	RARB
GLIQUIDONE	2	RARB
MBQ-167	1	RAC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
RARB	278	Binding:199, Functional:78, ADMET:1
RAC1	74	Binding:74
RNASE1	17	Binding:16, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNASE1	4.6.1.18	pancreatic ribonuclease
RAC1	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RARB	278

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

21 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)
KETOROLAC	4	RAC1
BEXAROTENE	4	RARB
AMOXICILLIN	4	RARB
ADAPALENE	4	RARB
TOLCAPONE	4	RARB
KETOCONAZOLE	4	RARB
CYCLOSPORINE	4	RARB
TAZAROTENE	4	RARB
TAMIBAROTENE	4	RARB
TRIFAROTENE	4	RARB
TRETINOIN	4	RARB
TROGLITAZONE	4	RARB
TROVAFLOXACIN	4	RARB
ALPROSTADIL	4	RARB
IBUPROFEN	4	RARB
ZAFIRLUKAST	4	RARB
ALITRETINOIN	4	RARB
SANGUINARIUM CHLORIDE	2	RAC1
CONESSINE	2	RARB
GLIQUIDONE	2	RARB
MBQ-167	1	RAC1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	RAC1, RARB
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	RNASE1
D	Druggable family + AlphaFold only, no drug	0
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)
RNASE1	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.