X-linked intellectual disability-short stature-overweight syndrome

Summary

X-linked intellectual disability-short stature-overweight syndrome (MONDO:0010496) is a disease caused by THOC2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: THOC2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 65
• Phenotypes (HPO): 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0025502	Overweight	Frequent (30-79%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000337	Broad forehead	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000733	Abnormal repetitive mannerisms	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000742	Self-mutilation	Occasional (5-29%)
HP:0000824	Decreased response to growth hormone stimulation test	Occasional (5-29%)
HP:0000954	Single transverse palmar crease	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001658	Myocardial infarction	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002171	Gliosis	Occasional (5-29%)
HP:0002206	Pulmonary fibrosis	Occasional (5-29%)
HP:0002487	Hyperkinetic movements	Occasional (5-29%)
HP:0004437	Cranial hyperostosis	Occasional (5-29%)
HP:0006986	Upper limb spasticity	Occasional (5-29%)
HP:0007033	Cerebellar dysplasia	Occasional (5-29%)
HP:0008734	Decreased testicular size	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked intellectual disability-short stature-overweight syndrome
Mondo ID	MONDO:0010496
OMIM	300957
Orphanet	457240
DOID	DOID:0112056
UMLS	C0796218
MedGen	901885
GARD	0017800
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked 12, X-linked recessive · intellectual disability, X-linked 12 · intellectual disability, X-linked type 12 · mental retardation, X-linked 12 · mental retardation, X-linked 35 · mental retardation, X-linked type 12 · MRX12

Data availability: 65 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 › X-linked intellectual disability-short stature-overweight syndrome

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, 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, intellectual disability, autosomal dominant 48, 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

65 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 9 likely pathogenic, 7 pathogenic, 4 benign/likely benign, 3 benign, 3 conflicting classifications of pathogenicity, 2 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208523	NM_001081550.2(THOC2):c.1313T>C (p.Leu438Pro)	THOC2	Pathogenic	no assertion criteria provided
208524	NM_001081550.2(THOC2):c.937C>T (p.Leu313Phe)	THOC2	Pathogenic	no assertion criteria provided
208525	NM_001081550.2(THOC2):c.3034T>C (p.Ser1012Pro)	THOC2	Pathogenic	no assertion criteria provided
208526	NM_001081550.2(THOC2):c.2399T>C (p.Ile800Thr)	THOC2	Pathogenic	no assertion criteria provided
3362897	THOC2, 2.4-KB DEL, EX37-38DEL	THOC2	Pathogenic	no assertion criteria provided
488430	NM_001081550.2(THOC2):c.2087C>T (p.Thr696Ile)	THOC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488431	NM_001081550.2(THOC2):c.2138G>A (p.Gly713Asp)	THOC2	Pathogenic	no assertion criteria provided
488432	NM_001081550.2(THOC2):c.3559C>T (p.His1187Tyr)	THOC2	Pathogenic/Likely pathogenic	no assertion criteria provided
488434	NM_001081550.2(THOC2):c.4450-2A>G	THOC2	Pathogenic	criteria provided, single submitter
1527937	NM_001081550.2(THOC2):c.1844G>A (p.Cys615Tyr)	THOC2	Likely pathogenic	criteria provided, single submitter
1700225	NM_001081550.2(THOC2):c.34T>C (p.Trp12Arg)	THOC2	Likely pathogenic	criteria provided, single submitter
1700228	NM_001081550.2(THOC2):c.2695T>C (p.Tyr899His)	THOC2	Likely pathogenic	criteria provided, single submitter
488433	NM_001081550.2(THOC2):c.3503+4A>C	THOC2	Likely pathogenic	no assertion criteria provided
488437	NM_001081550.2(THOC2):c.3323C>T (p.Ser1108Leu)	THOC2	Likely pathogenic	criteria provided, single submitter
804356	NM_001081550.2(THOC2):c.2642A>G (p.Tyr881Cys)	THOC2	Likely pathogenic	criteria provided, single submitter
807709	NM_001081550.2(THOC2):c.149A>C (p.Tyr50Ser)	THOC2	Likely pathogenic	criteria provided, single submitter
982367	NM_001081550.2(THOC2):c.1942G>T (p.Ala648Ser)	THOC2	Likely pathogenic	criteria provided, single submitter
984647	NM_001081550.2(THOC2):c.3305A>G (p.Tyr1102Cys)	THOC2	Likely pathogenic	no assertion criteria provided
488435	NM_001081550.2(THOC2):c.1550A>G (p.Tyr517Cys)	THOC2	Conflicting classifications of pathogenicity	no assertion criteria provided
488436	NM_001081550.2(THOC2):c.229C>T (p.Arg77Cys)	THOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804354	NM_001081550.2(THOC2):c.1996A>G (p.Asn666Asp)	THOC2	Conflicting classifications of pathogenicity	no assertion criteria provided
3775830	NM_001081550.2(THOC2):c.8C>T (p.Ala3Val)	LOC130068628	Uncertain significance	criteria provided, single submitter
1029050	NM_001081550.2(THOC2):c.195G>C (p.Gln65His)	THOC2	Uncertain significance	criteria provided, single submitter
1029051	NM_001081550.2(THOC2):c.2734G>C (p.Ala912Pro)	THOC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029052	NM_001081550.2(THOC2):c.2993G>A (p.Arg998His)	THOC2	Uncertain significance	criteria provided, single submitter
1033275	NM_001081550.2(THOC2):c.2414A>G (p.Asn805Ser)	THOC2	Uncertain significance	criteria provided, single submitter
1709280	NM_001081550.2(THOC2):c.2983T>C (p.Tyr995His)	THOC2	Uncertain significance	criteria provided, single submitter
1802559	NM_001081550.2(THOC2):c.623A>G (p.Asn208Ser)	THOC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805377	NM_001081550.2(THOC2):c.4318A>G (p.Ile1440Val)	THOC2	Uncertain significance	criteria provided, single submitter
2437079	NM_001081550.2(THOC2):c.4226G>A (p.Arg1409His)	THOC2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
THOC2	Strong	X-linked	X-linked intellectual disability-short stature-overweight syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THOC2	Orphanet:457240	X-linked intellectual disability-short stature-overweight syndrome
SIL1	Orphanet:559	Marinesco-Sjögren syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
THOC2	HGNC:19073	ENSG00000125676	Q8NI27	THO complex subunit 2	gencc,clinvar
SIL1	HGNC:24624	ENSG00000120725	Q9H173	Nucleotide exchange factor SIL1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THOC2	THO complex subunit 2	Component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA.
SIL1	Nucleotide exchange factor SIL1	Required for protein translocation and folding in the endoplasmic reticulum (ER).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THOC2	Other/Unknown	no		THO_THOC2_C, THO_THOC2_N, THOC2_N
SIL1	Other/Unknown	no		ARM-like, Nucleotide_exch_fac_Fes1, ARM-type_fold

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
oocyte	1
secondary oocyte	1
body of pancreas	1
islet of Langerhans	1
left testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THOC2	297	ubiquitous	marker	secondary oocyte, calcaneal tendon, oocyte
SIL1	251	ubiquitous	marker	islet of Langerhans, body of pancreas, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SIL1	4,196
THOC2	3,251

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
THOC2	Q8NI27	4
SIL1	Q9H173	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transport of Mature Transcript to Cytoplasm	1	380.7×	0.013	THOC2
RNA Polymerase II Transcription Termination	1	219.6×	0.013	THOC2
mRNA 3’-end processing	1	196.9×	0.013	THOC2
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	152.3×	0.013	THOC2
Processing of Capped Intron-Containing Pre-mRNA	1	82.2×	0.019	THOC2
Metabolism of RNA	1	41.7×	0.032	THOC2
RNA Polymerase II Transcription	1	22.5×	0.051	THOC2
Gene expression (Transcription)	1	17.8×	0.056	THOC2

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
regulation of mRNA export from nucleus	1	1053.2×	0.005	THOC2
stem cell division	1	936.2×	0.005	THOC2
cotranslational protein targeting to membrane	1	842.6×	0.005	SIL1
generation of neurons	1	766.0×	0.005	THOC2
blastocyst development	1	337.0×	0.007	THOC2
poly(A)+ mRNA export from nucleus	1	337.0×	0.007	THOC2
mRNA export from nucleus	1	147.8×	0.014	THOC2
neuron development	1	127.7×	0.014	THOC2
negative regulation of neuron projection development	1	118.7×	0.014	THOC2
cell morphogenesis	1	78.8×	0.019	THOC2
protein folding	1	51.7×	0.026	SIL1
RNA splicing	1	44.1×	0.027	THOC2
regulation of gene expression	1	41.7×	0.027	THOC2
mRNA processing	1	39.4×	0.027	THOC2
intracellular protein transport	1	32.4×	0.031	SIL1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THOC2	0	0
SIL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
THOC2	1	Binding:1

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	2	THOC2, SIL1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
THOC2	1	—
SIL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.