intellectual disability, X-linked 19

disease

On this page

Also known as intellectual developmental disorder, X-linked 19, X-linked dominantintellectual disability, X-linked type 19mental retardation, X-linked 19mental retardation, X-linked type 19MRX19non-syndromic X-linked intellectual disability caused by mutation in RPS6KA3RPS6KA3 non-syndromic X-linked intellectual disability

Summary

intellectual disability, X-linked 19 (MONDO:0010447) is a disease caused by RPS6KA3 (GenCC Strong), with 2 cohort genes.

At a glance

Causal gene: RPS6KA3 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 264

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 19
Mondo ID	MONDO:0010447
MeSH	C563141
OMIM	300844
DOID	DOID:0112019
UMLS	C0796225
MedGen	208676
GARD	0022687
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked 19, X-linked dominant · intellectual disability, X-linked 19 · intellectual disability, X-linked type 19 · mental retardation, X-linked 19 · mental retardation, X-linked type 19 · MRX19 · non-syndromic X-linked intellectual disability caused by mutation in RPS6KA3 · RPS6KA3 non-syndromic X-linked intellectual disability

Data availability: 264 ClinVar variants · 1 GenCC gene-disease record.

Disease family

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 › intellectual disability, X-linked 19

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

264 retrieved; paginated sample, class counts are floors:

86 likely benign, 61 uncertain significance, 39 benign, 36 pathogenic, 15 benign/likely benign, 13 conflicting classifications of pathogenicity, 10 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3243867	NC_000023.10:g.(?17393881)(20284750_?)del	ADGRG2	Pathogenic	criteria provided, single submitter
1073446	NC_000023.10:g.(?20204394)(20206108_?)del	RPS6KA3	Pathogenic	criteria provided, single submitter
1074355	NM_004586.3(RPS6KA3):c.251del (p.Phe83_Leu84insTer)	RPS6KA3	Pathogenic	criteria provided, single submitter
11658	NM_004586.3(RPS6KA3):c.2186G>A (p.Arg729Gln)	RPS6KA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11659	NM_004586.3(RPS6KA3):c.1147C>T (p.Arg383Trp)	RPS6KA3	Pathogenic	no assertion criteria provided
1451836	NM_004586.3(RPS6KA3):c.740dup (p.Ser248fs)	RPS6KA3	Pathogenic	criteria provided, single submitter
1455251	NM_004586.3(RPS6KA3):c.770_773del (p.Leu257fs)	RPS6KA3	Pathogenic	criteria provided, single submitter
1476999	NM_004586.3(RPS6KA3):c.2142_2145dup (p.Pro716fs)	RPS6KA3	Pathogenic	criteria provided, single submitter
1686133	NM_004586.3(RPS6KA3):c.1740del (p.Cys579_Tyr580insTer)	RPS6KA3	Pathogenic	criteria provided, single submitter
1805036	NM_004586.3(RPS6KA3):c.889_890del (p.Leu298fs)	RPS6KA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2050023	NM_004586.3(RPS6KA3):c.1814G>A (p.Gly605Asp)	RPS6KA3	Pathogenic	criteria provided, single submitter
2106659	NM_004586.3(RPS6KA3):c.709C>T (p.Pro237Ser)	RPS6KA3	Pathogenic	criteria provided, single submitter
2108477	NM_004586.3(RPS6KA3):c.1602+2dup	RPS6KA3	Pathogenic	criteria provided, single submitter
212067	NM_004586.3(RPS6KA3):c.1304_1307del (p.Val435fs)	RPS6KA3	Pathogenic	criteria provided, multiple submitters, no conflicts
2138486	NM_004586.3(RPS6KA3):c.2005_2008del (p.Thr669fs)	RPS6KA3	Pathogenic	criteria provided, single submitter
2138487	NM_004586.3(RPS6KA3):c.845+5G>A	RPS6KA3	Pathogenic	criteria provided, single submitter
225519	NM_004586.3(RPS6KA3):c.913C>T (p.Arg305Ter)	RPS6KA3	Pathogenic	criteria provided, multiple submitters, no conflicts
2425178	NC_000023.10:g.(?20173516)(20174387_?)del	RPS6KA3	Pathogenic	criteria provided, single submitter
2944446	NM_004586.3(RPS6KA3):c.1566_1567insTG (p.Ile523Ter)	RPS6KA3	Pathogenic	criteria provided, single submitter
2950102	NM_004586.3(RPS6KA3):c.955G>T (p.Glu319Ter)	RPS6KA3	Pathogenic	criteria provided, single submitter
2951625	NM_004586.3(RPS6KA3):c.2093dup (p.Val699fs)	RPS6KA3	Pathogenic	criteria provided, single submitter
29931	NM_004586.3(RPS6KA3):c.455GAG[1] (p.Gly153del)	RPS6KA3	Pathogenic	no assertion criteria provided
29932	NM_004586.3(RPS6KA3):c.343A>T (p.Thr115Ser)	RPS6KA3	Pathogenic	no assertion criteria provided
3754252	NM_004586.3(RPS6KA3):c.283C>T (p.Gln95Ter)	RPS6KA3	Pathogenic	criteria provided, single submitter
3754683	NM_004586.3(RPS6KA3):c.755G>A (p.Trp252Ter)	RPS6KA3	Pathogenic	criteria provided, single submitter
3756871	NM_004586.3(RPS6KA3):c.2162_2168del (p.Val721fs)	RPS6KA3	Pathogenic	criteria provided, single submitter
3757013	NM_004586.3(RPS6KA3):c.1740C>A (p.Tyr580Ter)	RPS6KA3	Pathogenic	criteria provided, single submitter
3759341	NM_004586.3(RPS6KA3):c.909_910insT (p.Lys304Ter)	RPS6KA3	Pathogenic	criteria provided, single submitter
3760034	NM_004586.3(RPS6KA3):c.1615_1616del (p.Asp539fs)	RPS6KA3	Pathogenic	criteria provided, single submitter
426465	NM_004586.3(RPS6KA3):c.1894C>T (p.Arg632Ter)	RPS6KA3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
RPS6KA3	Strong	X-linked	intellectual disability, X-linked 19	9

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
ADGRG2	Orphanet:48	Congenital bilateral absence of vas deferens

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
RPS6KA3	HGNC:10432	ENSG00000177189	P51812	Ribosomal protein S6 kinase alpha-3	gencc,clinvar
ADGRG2	HGNC:4516	ENSG00000173698	Q8IZP9	Adhesion G-protein coupled receptor G2	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…
ADGRG2	Adhesion G-protein coupled receptor G2	Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as dehydroepiandrosterone (DHEA; also named 3beta-hydroxyandrost-5-en-17-one) and androstenedione.

Protein-family classification

Druggable: 2 · 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
Kinase	1	13.9×	0.082
GPCR	1	12.0×	0.082

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
ADGRG2	GPCR	yes		GPS, GPCR_2_secretin-like, GPCR_2-like_7TM

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
cartilage tissue	1
colonic mucosa	1
mucosa of sigmoid colon	1
caput epididymis	1
corpus epididymis	1
parotid gland	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
ADGRG2	182	broad	marker	corpus epididymis, caput epididymis, parotid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPS6KA3	2,713
ADGRG2	723

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPS6KA3	P51812	15

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADGRG2	Q8IZP9	62.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. 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
CREB phosphorylation	1	1631.4×	0.011	RPS6KA3
RSK activation	1	1427.5×	0.011	RPS6KA3
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	878.5×	0.011	RPS6KA3
Gastrin-CREB signalling pathway via PKC and MAPK	1	878.5×	0.011	RPS6KA3
ERK/MAPK targets	1	671.8×	0.011	RPS6KA3
MAPK targets/ Nuclear events mediated by MAP kinases	1	543.8×	0.011	RPS6KA3
Nuclear Events (kinase and transcription factor activation)	1	346.1×	0.011	RPS6KA3
MAP kinase activation	1	308.6×	0.011	RPS6KA3
Interleukin-17 signaling	1	253.8×	0.011	RPS6KA3
Recycling pathway of L1	1	223.9×	0.011	RPS6KA3
Toll Like Receptor 10 (TLR10) Cascade	1	215.5×	0.011	RPS6KA3
Toll Like Receptor 5 (TLR5) Cascade	1	215.5×	0.011	RPS6KA3
Post NMDA receptor activation events	1	203.9×	0.011	RPS6KA3
MyD88 cascade initiated on plasma membrane	1	203.9×	0.011	RPS6KA3
Signaling by NTRK1 (TRKA)	1	196.9×	0.011	RPS6KA3
Toll Like Receptor 3 (TLR3) Cascade	1	193.6×	0.011	RPS6KA3
TRIF (TICAM1)-mediated TLR4 signaling	1	190.3×	0.011	RPS6KA3
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	190.3×	0.011	RPS6KA3
MyD88 dependent cascade initiated on endosome	1	190.3×	0.011	RPS6KA3
MyD88-independent TLR4 cascade	1	184.2×	0.011	RPS6KA3
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	184.2×	0.011	RPS6KA3
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.011	RPS6KA3
Signaling by NTRKs	1	181.3×	0.011	RPS6KA3
Toll Like Receptor 9 (TLR9) Cascade	1	175.7×	0.011	RPS6KA3
Toll Like Receptor TLR6:TLR2 Cascade	1	175.7×	0.011	RPS6KA3
Toll Like Receptor 2 (TLR2) Cascade	1	173.0×	0.011	RPS6KA3
Toll Like Receptor TLR1:TLR2 Cascade	1	167.9×	0.011	RPS6KA3
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	152.3×	0.012	RPS6KA3
Cellular Senescence	1	137.6×	0.013	RPS6KA3
Toll Like Receptor 4 (TLR4) Cascade	1	131.3×	0.013	RPS6KA3

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 translation in response to stress	1	2808.7×	0.007	RPS6KA3
TORC1 signaling	1	401.2×	0.021	RPS6KA3
toll-like receptor signaling pathway	1	300.9×	0.021	RPS6KA3
positive regulation of cell differentiation	1	133.8×	0.030	RPS6KA3
positive regulation of cell growth	1	91.6×	0.030	RPS6KA3
spermatid development	1	72.6×	0.030	ADGRG2
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.030	ADGRG2
skeletal system development	1	62.9×	0.030	RPS6KA3
response to lipopolysaccharide	1	62.4×	0.030	RPS6KA3
central nervous system development	1	57.7×	0.030	RPS6KA3
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.030	ADGRG2
chemical synaptic transmission	1	38.6×	0.041	RPS6KA3
cell surface receptor signaling pathway	1	32.0×	0.045	ADGRG2
G protein-coupled receptor signaling pathway	1	18.1×	0.067	ADGRG2
spermatogenesis	1	17.6×	0.067	ADGRG2
negative regulation of apoptotic process	1	17.4×	0.067	RPS6KA3
regulation of DNA-templated transcription	1	15.8×	0.070	RPS6KA3
signal transduction	1	8.0×	0.127	RPS6KA3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	RPS6KA3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
RPS6KA3	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPS6KA3	46	4
ADGRG2	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
ENZASTAURIN	3	RPS6KA3
FASUDIL	3	RPS6KA3
ALVOCIDIB	3	RPS6KA3
ALISERTIB	3	RPS6KA3
DOVITINIB	3	RPS6KA3
LESTAURTINIB	3	RPS6KA3
RUBOXISTAURIN	3	RPS6KA3
PAMAPIMOD	2	RPS6KA3
MOLIBRESIB	2	RPS6KA3
LUTEOLIN	2	RPS6KA3
SU-014813	2	RPS6KA3
ILORASERTIB	2	RPS6KA3
LAUROGUADINE	2	RPS6KA3
FISETIN	2	RPS6KA3
LY-2090314	2	RPS6KA3
CERDULATINIB	2	RPS6KA3
R-406	2	RPS6KA3
AT-9283	2	RPS6KA3
PICTILISIB	2	RPS6KA3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RPS6KA3	770	Binding:768, Functional:1, ADMET:1
ADGRG2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPS6KA3	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RPS6KA3	770

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

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
ENZASTAURIN	3	RPS6KA3
FASUDIL	3	RPS6KA3
ALVOCIDIB	3	RPS6KA3
ALISERTIB	3	RPS6KA3
DOVITINIB	3	RPS6KA3
LESTAURTINIB	3	RPS6KA3
RUBOXISTAURIN	3	RPS6KA3
PAMAPIMOD	2	RPS6KA3
MOLIBRESIB	2	RPS6KA3
LUTEOLIN	2	RPS6KA3
SU-014813	2	RPS6KA3
ILORASERTIB	2	RPS6KA3
LAUROGUADINE	2	RPS6KA3
FISETIN	2	RPS6KA3
LY-2090314	2	RPS6KA3
CERDULATINIB	2	RPS6KA3
R-406	2	RPS6KA3
AT-9283	2	RPS6KA3
PICTILISIB	2	RPS6KA3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RPS6KA3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADGRG2
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)
ADGRG2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: RPS6KA3, ADGRG2