Specific learning disability

disease

On this page

Also known as specific learning difficultyspecific learning disorder

Summary

Specific learning disability (MONDO:0016225) is a disease with 15 cohort genes and 21 clinical trials.

At a glance

Cohort genes: 15
ClinVar variants: 42
Clinical trials: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	specific learning disability
Mondo ID	MONDO:0016225
MeSH	D000067559
Orphanet	211047
UMLS	C4025790
MedGen	871302
Is cancer (heuristic)	no

Also known as: specific learning difficulty · specific learning disorder

Data availability: 42 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › specific learning disability

Subtypes (2): specific language disorder, non-verbal learning 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

42 retrieved; paginated sample, class counts are floors:

22 pathogenic, 11 uncertain significance, 6 likely pathogenic, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
267840	46;XY;t(15;17)(q24;q21.3)dn		Pathogenic	criteria provided, single submitter
267841	46;XX;t(7;13)(p13;q34)dn		Pathogenic	criteria provided, single submitter
267870	46;XX;t(11;12)(p12;p12.1)dn		Pathogenic	criteria provided, single submitter
267882	46;XX;inv(7)(q11.23q36.3)dn		Pathogenic	criteria provided, single submitter
268035	46;XX;t(19;21)(q13.3;q22.3)dn		Pathogenic	criteria provided, single submitter
268036	46;XX;t(2;10)(q22;22.3)dn		Pathogenic	criteria provided, single submitter
268039	46;XY;t(3;18)(q13.31;q22.1)dn		Pathogenic	criteria provided, single submitter
1700601	NM_014921.5(ADGRL1):c.3391C>T (p.Arg1131Ter)	ADGRL1	Pathogenic	criteria provided, single submitter
1700606	NM_014921.5(ADGRL1):c.3517C>T (p.Arg1173Ter)	ADGRL1	Pathogenic	criteria provided, single submitter
626905	NM_001195305.3(BBIP1):c.109C>T (p.Gln37Ter)	BBIP1	Pathogenic	no assertion criteria provided
1332907	NM_022552.5(DNMT3A):c.1647C>A (p.Cys549Ter)	DNMT3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1330177	GRCh37/hg19 19p13.11-q13.2(chr19:19546923-41313229)x3	FBL	Pathogenic	criteria provided, single submitter
813003	NM_014727.3(KMT2B):c.3143_3149del (p.Gly1048fs)	KMT2B	Pathogenic	no assertion criteria provided
917742	NM_002745.5(MAPK1):c.221T>A (p.Ile74Asn)	MAPK1	Pathogenic	criteria provided, single submitter
917743	NM_002745.5(MAPK1):c.238C>T (p.His80Tyr)	MAPK1	Pathogenic	criteria provided, multiple submitters, no conflicts
917744	NM_002745.5(MAPK1):c.521C>T (p.Ala174Val)	MAPK1	Pathogenic	criteria provided, multiple submitters, no conflicts
917745	NM_002745.5(MAPK1):c.952G>A (p.Asp318Asn)	MAPK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
917746	NM_002745.5(MAPK1):c.953A>G (p.Asp318Gly)	MAPK1	Pathogenic	criteria provided, multiple submitters, no conflicts
917748	NM_002745.5(MAPK1):c.964G>C (p.Glu322Gln)	MAPK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
917749	NM_002745.5(MAPK1):c.968C>G (p.Pro323Arg)	MAPK1	Pathogenic	criteria provided, single submitter
983496	NM_001382637.1(OTUD7A):c.697C>T (p.Leu233Phe)	OTUD7A	Pathogenic	no assertion criteria provided
1703558	GRCh37/hg19 10q23.31(chr10:89698323-90252519)	PTEN	Pathogenic	no assertion criteria provided
40554	NM_002834.5(PTPN11):c.1493G>T (p.Arg498Leu)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
1180447	NM_012479.4(YWHAG):c.89dup (p.Thr31fs)	YWHAG	Pathogenic	no assertion criteria provided
267818	46;X;t(Y;3)(p11.2;p12.3)dn		Likely pathogenic	criteria provided, single submitter
267834	46;X;t(Y;16)(q11.23;p11.2);t(6;21)(p21.3;p13)dn		Likely pathogenic	criteria provided, single submitter
267875	46;XX;t(10;14)(p13;q21)dn		Likely pathogenic	criteria provided, single submitter
267905	46;XY;t(4;14;4;1)(q28.2;q13.1;28.2q21;p32.3)dn		Likely pathogenic	criteria provided, single submitter
374121	NM_004586.3(RPS6KA3):c.533C>G (p.Ala178Gly)	RPS6KA3	Likely pathogenic	criteria provided, single submitter
812998	NM_001199107.2(TBC1D24):c.901C>T (p.Gln301Ter)	TBC1D24	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 45 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
YWHAG	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
KMT2B	Orphanet:528084	Non-specific syndromic intellectual disability
KMT2B	Orphanet:589618	Dystonia 28
ADGRL1	Orphanet:528084	Non-specific syndromic intellectual disability
BBIP1	Orphanet:110	Bardet-Biedl 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
TBC1D24	Orphanet:163727	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome
TBC1D24	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
TBC1D24	Orphanet:352582	Familial infantile myoclonic epilepsy
TBC1D24	Orphanet:352587	Focal epilepsy-intellectual disability-cerebro-cerebellar malformation
TBC1D24	Orphanet:352596	Progressive myoclonic epilepsy with dystonia
TBC1D24	Orphanet:79500	DOORS syndrome
TBC1D24	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TBC1D24	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
PDPN	Orphanet:1606	1p36 deletion syndrome
DNMT3A	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
DNMT3A	Orphanet:404443	Tatton-Brown-Rahman syndrome
DNMT3A	Orphanet:658595	DNMT3A-related microcephalic dwarfism
DNMT3A	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
GHR	Orphanet:314802	Short stature due to partial GHR deficiency
GHR	Orphanet:633	Laron syndrome
MAPK1	Orphanet:261330	Distal 22q11.2 microdeletion syndrome
PTEN	Orphanet:109	Bannayan-Riley-Ruvalcaba syndrome
PTEN	Orphanet:137608	Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
PTEN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PTEN	Orphanet:201	Cowden syndrome
PTEN	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
PTEN	Orphanet:2969	Proteus-like syndrome
PTEN	Orphanet:494547	Squamous cell carcinoma of the hypopharynx
PTEN	Orphanet:494550	Squamous cell carcinoma of the larynx
PTEN	Orphanet:500464	Squamous cell carcinoma of the nasal cavity and paranasal sinuses
PTEN	Orphanet:500478	Squamous cell carcinoma of the oropharynx
PTEN	Orphanet:502363	Squamous cell carcinoma of the oral cavity
PTEN	Orphanet:502366	Squamous cell carcinoma of the lip
PTEN	Orphanet:65285	Lhermitte-Duclos disease
PTEN	Orphanet:79076	Juvenile polyposis of infancy
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

15 cohort genes, 15 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	15

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPS6KA3	HGNC:10432	ENSG00000177189	P51812	Ribosomal protein S6 kinase alpha-3	clinvar
YWHAG	HGNC:12852	ENSG00000170027	P61981	14-3-3 protein gamma	clinvar
KMT2B	HGNC:15840	ENSG00000272333	Q9UMN6	Histone-lysine N-methyltransferase 2B	clinvar
OTUD7A	HGNC:20718	ENSG00000169918	Q8TE49	OTU domain-containing protein 7A	clinvar
ADGRL1	HGNC:20973	ENSG00000072071	O94910	Adhesion G protein-coupled receptor L1	clinvar
BBIP1	HGNC:28093	ENSG00000214413	A8MTZ0	BBSome-interacting protein 1	clinvar
IQSEC2	HGNC:29059	ENSG00000124313	Q5JU85	IQ motif and SEC7 domain-containing protein 2	clinvar
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	clinvar
PDPN	HGNC:29602	ENSG00000162493	Q86YL7	Podoplanin	clinvar
DNMT3A	HGNC:2978	ENSG00000119772	Q9Y6K1	DNA (cytosine-5)-methyltransferase 3A	clinvar
FBL	HGNC:3599	ENSG00000105202	P22087	rRNA 2’-O-methyltransferase fibrillarin	clinvar
GHR	HGNC:4263	ENSG00000112964	P10912	Growth hormone receptor	clinvar
MAPK1	HGNC:6871	ENSG00000100030	P28482	Mitogen-activated protein kinase 1	clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
YWHAG	14-3-3 protein gamma	Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways.
KMT2B	Histone-lysine N-methyltransferase 2B	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4) via a non-processive mechanism.
OTUD7A	OTU domain-containing protein 7A	Deubiquitinase, which cleaves ‘Lys-11’-linked polyubiquitin chains.
ADGRL1	Adhesion G protein-coupled receptor L1	Calcium-independent receptor of high affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells.
BBIP1	BBSome-interacting protein 1	The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia.
IQSEC2	IQ motif and SEC7 domain-containing protein 2	Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins.
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
PDPN	Podoplanin	Mediates effects on cell migration and adhesion through its different partners.
DNMT3A	DNA (cytosine-5)-methyltransferase 3A	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.
FBL	rRNA 2’-O-methyltransferase fibrillarin	S-adenosyl-L-methionine-dependent methyltransferase that has the ability to methylate both RNAs and proteins.
GHR	Growth hormone receptor	Receptor for pituitary gland growth hormone (GH1) involved in regulating postnatal body growth.
MAPK1	Mitogen-activated protein kinase 1	Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 7 · Difficult: 3 · Unknown: 5 · Druggable fraction: 0.47

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
Phosphatase	2	11.2×	0.107
Complement	1	17.9×	0.218
Kinase	2	3.7×	0.267
Antibody/Immunoglobulin	1	1.9×	0.675
GPCR	1	1.6×	0.675
Scaffold/PPI	1	1.1×	0.675
Transcription factor	2	1.1×	0.675
Other/Unknown	5	0.6×	0.978

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPS6KA3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
YWHAG	Other/Unknown	no		14-3-3, 14-3-3_CS, 14-3-3_domain
KMT2B	Transcription factor	no		SET_dom, Znf_PHD, Znf_CXXC
OTUD7A	Transcription factor	no		Znf_A20, OTU_dom, OTU_Deubiquitinase
ADGRL1	GPCR	yes		GPS, GPCR_2_secretin-like, Lectin_gal-bd_dom
BBIP1	Other/Unknown	no		BBIP10
IQSEC2	Scaffold/PPI	no		Sec7_dom, PH_domain, PH-like_dom_sf
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
PDPN	Other/Unknown	no		Podoplanin_domain
DNMT3A	Complement	yes	2.1.1.37	PWWP_dom, C5_MeTfrase, C5_DNA_meth_AS
FBL	Other/Unknown	no		Fibrillarin, Fibrillarin_CS, SAM-dependent_MTases_sf
GHR	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold
MAPK1	Kinase	yes	2.7.11.24	Prot_kinase_dom, MAP_kinase_CS, Ser/Thr_kinase_AS
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

13 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)	15
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	3
middle temporal gyrus	3
cartilage tissue	2
endothelial cell	2
cerebellar cortex	2
right hemisphere of cerebellum	2
sperm	2
ganglionic eminence	2
colonic mucosa	1
mucosa of sigmoid colon	1
lateral nuclear group of thalamus	1
pons	1
substantia nigra pars compacta	1
left testis	1
lower esophagus mucosa	1
right testis	1
cerebellum	1
buccal mucosa cell	1
epithelium of nasopharynx	1
cerebellar hemisphere	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPS6KA3	285	ubiquitous	marker	cartilage tissue, mucosa of sigmoid colon, colonic mucosa
YWHAG	266	ubiquitous	marker	lateral nuclear group of thalamus, pons, substantia nigra pars compacta
KMT2B	269	ubiquitous	marker	right testis, left testis, lower esophagus mucosa
OTUD7A	178	broad	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
ADGRL1	134	broad	marker	right hemisphere of cerebellum, cerebellum, cerebellar cortex
BBIP1	288	ubiquitous	marker	epithelium of nasopharynx, buccal mucosa cell, sperm
IQSEC2	236	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TBC1D24	227	ubiquitous	marker	parotid gland, Brodmann (1909) area 23, middle temporal gyrus
PDPN	248	ubiquitous	marker	tibia, primordial germ cell in gonad, cartilage tissue
DNMT3A	223	ubiquitous	marker	sural nerve, ganglionic eminence, ventricular zone
FBL	134	ubiquitous	marker	ganglionic eminence, left ovary, ovary
GHR	248	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, biceps brachii
MAPK1	299	ubiquitous	marker	middle temporal gyrus, postcentral gyrus, Brodmann (1909) area 23
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTEN	11,626
MAPK1	8,003
PTPN11	6,009
FBL	5,696
DNMT3A	4,771
YWHAG	3,643
RPS6KA3	2,713
KMT2B	2,639
PDPN	2,137
ADGRL1	1,697

Intra-cohort edges

A	B	Sources
GHR	PTPN11	biogrid_interaction
IQSEC2	YWHAG	intact
MAPK1	RPS6KA3	biogrid_interaction, intact
OTUD7A	PTEN	intact
OTUD7A	YWHAG	intact
PTPN11	RPS6KA3	string_interaction

Structural data

PDB: 13 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAPK1	P28482	160
PTPN11	Q06124	115
DNMT3A	Q9Y6K1	43
YWHAG	P61981	22
RPS6KA3	P51812	15
FBL	P22087	12
PTEN	P60484	12
GHR	P10912	11
PDPN	Q86YL7	6
KMT2B	Q9UMN6	4
IQSEC2	Q5JU85	2
OTUD7A	Q8TE49	1
BBIP1	A8MTZ0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBC1D24	Q9ULP9	84.46
ADGRL1	O94910	70.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 286. Enrichment computed across 15 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RSK activation	2	219.6×	0.007	RPS6KA3, MAPK1
MAPK1 (ERK2) activation	2	175.7×	0.007	MAPK1, PTPN11
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	2	135.2×	0.007	RPS6KA3, MAPK1
Gastrin-CREB signalling pathway via PKC and MAPK	2	135.2×	0.007	RPS6KA3, MAPK1
Prolactin receptor signaling	2	117.1×	0.007	GHR, PTPN11
Spry regulation of FGF signaling	2	109.8×	0.007	MAPK1, PTPN11
ERK/MAPK targets	2	103.3×	0.007	RPS6KA3, MAPK1
MAPK targets/ Nuclear events mediated by MAP kinases	2	83.7×	0.009	RPS6KA3, MAPK1
Growth hormone receptor signaling	2	73.2×	0.010	GHR, MAPK1
Negative regulation of FGFR3 signaling	2	67.6×	0.011	MAPK1, PTPN11
Negative regulation of FGFR4 signaling	2	62.8×	0.012	MAPK1, PTPN11
Negative regulation of FGFR1 signaling	2	56.7×	0.012	MAPK1, PTPN11
Negative regulation of FGFR2 signaling	2	56.7×	0.012	MAPK1, PTPN11
Nuclear Events (kinase and transcription factor activation)	2	53.2×	0.013	RPS6KA3, MAPK1
GPVI-mediated activation cascade	2	47.5×	0.014	PDPN, PTPN11
MAP kinase activation	2	47.5×	0.014	RPS6KA3, MAPK1
Intrinsic Pathway for Apoptosis	2	45.0×	0.014	YWHAG, MAPK1
Negative regulation of the PI3K/AKT network	2	42.9×	0.014	MAPK1, PTEN
Ovarian tumor domain proteases	2	42.9×	0.014	OTUD7A, PTEN
Interleukin-17 signaling	2	39.0×	0.016	RPS6KA3, MAPK1
phospho-PLA2 pathway	1	439.2×	0.017	MAPK1
PTEN Loss of Function in Cancer	1	439.2×	0.017	PTEN
Recycling pathway of L1	2	34.5×	0.017	RPS6KA3, MAPK1
Toll Like Receptor 10 (TLR10) Cascade	2	33.1×	0.017	RPS6KA3, MAPK1
Toll Like Receptor 5 (TLR5) Cascade	2	33.1×	0.017	RPS6KA3, MAPK1
Post NMDA receptor activation events	2	31.4×	0.017	RPS6KA3, MAPK1
MyD88 cascade initiated on plasma membrane	2	31.4×	0.017	RPS6KA3, MAPK1
Signaling by NTRK1 (TRKA)	2	30.3×	0.017	RPS6KA3, MAPK1
Toll Like Receptor 3 (TLR3) Cascade	2	29.8×	0.017	RPS6KA3, MAPK1
TRIF (TICAM1)-mediated TLR4 signaling	2	29.3×	0.017	RPS6KA3, MAPK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ERBB signaling pathway	2	449.4×	0.002	MAPK1, PTPN11
Bergmann glial cell differentiation	2	204.3×	0.006	MAPK1, PTPN11
hormone metabolic process	2	118.3×	0.012	GHR, PTPN11
positive regulation of intracellular signal transduction	2	86.4×	0.017	PTEN, PTPN11
positive regulation of excitatory postsynaptic potential	2	70.2×	0.019	TBC1D24, PTEN
insulin-like growth factor receptor signaling pathway	2	66.1×	0.019	GHR, MAPK1
regulation of response to nutrient levels	1	1123.5×	0.023	GHR
negative regulation of cortisol secretion	1	1123.5×	0.023	PTPN11
negative regulation of growth hormone secretion	1	1123.5×	0.023	PTPN11
regulation of myofibroblast contraction	1	1123.5×	0.023	PDPN
hormone-mediated signaling pathway	2	53.5×	0.023	GHR, PTPN11
cytosine metabolic process	1	561.7×	0.025	MAPK1
microvillus organization	1	561.7×	0.025	PTPN11
intestinal epithelial cell migration	1	561.7×	0.025	PTPN11
negative regulation of synaptic vesicle clustering	1	561.7×	0.025	PTEN
box C/D sno(s)RNA 3’-end processing	1	374.5×	0.025	FBL
cerebellar cortex formation	1	374.5×	0.025	PTPN11
regulation of translation in response to stress	1	374.5×	0.025	RPS6KA3
response to cycloheximide	1	374.5×	0.025	GHR
negative regulation of keratinocyte migration	1	374.5×	0.025	PTEN
lymphatic endothelial cell fate commitment	1	374.5×	0.025	PDPN
cardiac neural crest cell development involved in heart development	1	374.5×	0.025	MAPK1
interleukin-34-mediated signaling pathway	1	374.5×	0.025	MAPK1
actin-mediated cell contraction	1	374.5×	0.025	PDPN
positive regulation of cellular response to hypoxia	1	374.5×	0.025	DNMT3A
regulation of lamellipodium morphogenesis	1	374.5×	0.025	PDPN
positive regulation of cell differentiation	2	35.7×	0.025	RPS6KA3, GHR
epidermal growth factor receptor signaling pathway	2	33.0×	0.025	MAPK1, PTPN11
learning or memory	2	32.1×	0.025	MAPK1, PTEN
response to estradiol	2	26.4×	0.025	DNMT3A, GHR

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 11

Druggability breadth: 9 of 15 evidence-associated genes (60%) 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
MAPK1	PHENYLBUTAZONE
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAPK1	324	4
RPS6KA3	46	4
PTPN11	8	4
YWHAG	1	2
KMT2B	0	0
OTUD7A	0	0
ADGRL1	0	0
BBIP1	0	0
IQSEC2	0	0
TBC1D24	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	RPS6KA3
GILTERITINIB	4	RPS6KA3
BRIGATINIB	4	RPS6KA3
UPADACITINIB	4	RPS6KA3
NINTEDANIB	4	RPS6KA3
SUNITINIB	4	RPS6KA3
QUIZARTINIB	4	RPS6KA3
MIDOSTAURIN	4	RPS6KA3
PHENYLBUTAZONE	4	MAPK1
CANDESARTAN CILEXETIL	4	MAPK1
TELMISARTAN	4	MAPK1
PROGESTERONE	4	MAPK1
CLOTRIMAZOLE	4	MAPK1
LATANOPROST	4	MAPK1
OXAPROZIN	4	MAPK1
CARBAMAZEPINE	4	MAPK1
SALMETEROL XINAFOATE	4	MAPK1
BRETYLIUM TOSYLATE	4	MAPK1
CHLORMADINONE ACETATE	4	MAPK1
DROPERIDOL	4	MAPK1
PYRIDOSTIGMINE	4	MAPK1
IDARUBICIN	4	MAPK1
IODIPAMIDE	4	MAPK1
TETRABENAZINE	4	MAPK1
PRAMOXINE	4	MAPK1
ESCITALOPRAM OXALATE	4	MAPK1
NICARDIPINE HYDROCHLORIDE	4	MAPK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
MAPK1	1,369	Binding:1348, Functional:16, ADMET:5
RPS6KA3	770	Binding:768, Functional:1, ADMET:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
DNMT3A	120	Binding:118, ADMET:1, Functional:1
KMT2B	15	Binding:15
YWHAG	12	Binding:11, Functional:1
PTEN	8	Binding:8
GHR	2	Binding:2
FBL	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPS6KA3	2.7.11.1	non-specific serine/threonine protein kinase
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase
MAPK1	2.7.11.24	mitogen-activated protein kinase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RPS6KA3	770
DNMT3A	120
MAPK1	1,369
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; 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	RPS6KA3
GILTERITINIB	4	RPS6KA3
BRIGATINIB	4	RPS6KA3
UPADACITINIB	4	RPS6KA3
NINTEDANIB	4	RPS6KA3
SUNITINIB	4	RPS6KA3
QUIZARTINIB	4	RPS6KA3
MIDOSTAURIN	4	RPS6KA3
PHENYLBUTAZONE	4	MAPK1
CANDESARTAN CILEXETIL	4	MAPK1
TELMISARTAN	4	MAPK1
PROGESTERONE	4	MAPK1
CLOTRIMAZOLE	4	MAPK1
LATANOPROST	4	MAPK1
OXAPROZIN	4	MAPK1
CARBAMAZEPINE	4	MAPK1
SALMETEROL XINAFOATE	4	MAPK1
BRETYLIUM TOSYLATE	4	MAPK1
CHLORMADINONE ACETATE	4	MAPK1
DROPERIDOL	4	MAPK1
PYRIDOSTIGMINE	4	MAPK1
IDARUBICIN	4	MAPK1
IODIPAMIDE	4	MAPK1
TETRABENAZINE	4	MAPK1
PRAMOXINE	4	MAPK1
ESCITALOPRAM OXALATE	4	MAPK1
NICARDIPINE HYDROCHLORIDE	4	MAPK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	RPS6KA3, MAPK1, PTPN11
B	Phased (≥1) drug, not yet approved	1	YWHAG
C	Druggable family + PDB, no drug	3	DNMT3A, GHR, PTEN
D	Druggable family + AlphaFold only, no drug	1	ADGRL1
E	Difficult family or no structure, no drug	7	KMT2B, OTUD7A, BBIP1, IQSEC2, TBC1D24, PDPN, FBL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNMT3A	120	—
KMT2B	15	—
OTUD7A	0	—
ADGRL1	0	—
BBIP1	0	—
IQSEC2	0	—
TBC1D24	0	—
PDPN	0	—
FBL	1	—
GHR	2	—
PTEN	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 21.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	21

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05780853	Not specified	RECRUITING	A Game-based Neurodevelopmental Assessment for Young Children
NCT05872737	Not specified	RECRUITING	FAB Programme for Parents of Children With NDD
NCT06086951	Not specified	RECRUITING	Pai.ACT - An Artificial Intelligence Driven Chatbot Assisted ACT
NCT06713863	Not specified	RECRUITING	Intervention Effectiveness Study of BEtter AT LEarning (BEATLE)- Digital Neuropsychological Rehabilitation Program
NCT07488650	Not specified	NOT_YET_RECRUITING	Children With Specific Learning Disabilities and Exercise
NCT07611942	Not specified	NOT_YET_RECRUITING	Plaque Removal Efficiency in Children With Specific Learning Disabilities
NCT07611981	Not specified	NOT_YET_RECRUITING	Dental Caries and Oral Hygiene Status in Children With Specific Learning Disabilities
NCT03261076	Not specified	UNKNOWN	Reading Remediation and Outcomes in Detention
NCT04122820	Not specified	UNKNOWN	Ambulatory Screening for Specific Learning Disabilities (SLD) and Developmental Coordination Disorder (DCD).
NCT04783987	Not specified	UNKNOWN	Single and Dual Task Gait Parameters in Children With Specific Learning Difficulties
NCT05319197	Not specified	COMPLETED	HAND FUNCTIONS OF CHILDREN WITH A SPECIFIC LEARNING DISORDER
NCT05787483	Not specified	COMPLETED	Biopsychosocial Outcomes of Mindfulness-based Instruction
NCT05902143	Not specified	UNKNOWN	Fine Motor Function in Children With Specific Learning Disorders
NCT05923645	Not specified	UNKNOWN	Efficacy of rTMS as an Adjunct to AI Enabled Remedial Intervention in Children With Dyslexia
NCT05998083	Not specified	COMPLETED	The Effectiveness of Purposeful Exercises in Children Diagnosed With Special Learning Disabilities
NCT06112483	Not specified	UNKNOWN	SWELE Program: An Unstructured Outdoor Play With Mindfulness-based Interventions to Promote Mental Health Among Students With Special Education Needs
NCT06262646	Not specified	COMPLETED	Video-conferencing FACT for Young Children With Special Needs
NCT06878690	Not specified	COMPLETED	Sleep Disorders in Specific Learning Disabilities
NCT07054164	Not specified	COMPLETED	Effect of Dual-Task Aerobic Exercise on Children With Specific Learning Disorder
NCT07240142	Not specified	COMPLETED	Neurotransmitter Levels in Children With Specific Learning Disorder
NCT07376902	Not specified	COMPLETED	White Noise in SLD and ADHD

Cohort genes: RPS6KA3, YWHAG, KMT2B, OTUD7A, ADGRL1, BBIP1, IQSEC2, TBC1D24, PDPN, DNMT3A, FBL, GHR, MAPK1, PTEN, PTPN11