intellectual disability, X-linked 30

Summary

intellectual disability, X-linked 30 (MONDO:0010361) is a disease caused by PAK3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PAK3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 63

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 30
Mondo ID	MONDO:0010361
OMIM	300558
DOID	DOID:0112051
UMLS	C0796237
MedGen	163235
GARD	0022682
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked 30, X-linked recessive · intellectual disability, X-linked 30 · intellectual disability, X-linked type 30 · mental retardation, X-linked 30 · mental retardation, X-linked 47 · mental retardation, X-linked type 30 · MRX30 · non-syndromic X-linked intellectual disability caused by mutation in PAK3 · PAK3 non-syndromic X-linked intellectual disability

Data availability: 63 ClinVar variants · 4 GenCC gene-disease records.

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 30

Related subtypes (51): intellectual disability, X-linked 23, intellectual disability, X-linked 20, intellectual disability, X-linked 14, intellectual disability, X-linked 50, intellectual disability, X-linked 21, intellectual disability, X-linked 58, intellectual disability, X-linked 72, intellectual disability, X-linked 53, intellectual disability, X-linked 73, intellectual disability, X-linked 42, intellectual disability, X-linked 63, intellectual disability, X-linked, with or without seizures, ARX-related, intellectual disability, X-linked 2, intellectual disability, X-linked 81, intellectual disability, X-linked 46, intellectual disability, X-linked 77, intellectual disability, X-linked 45, intellectual disability, X-linked 84, intellectual disability, X-linked 82, intellectual disability, X-linked 91, intellectual disability, X-linked 93, chromosome Xp11.22 duplication syndrome, intellectual disability, X-linked 95, intellectual disability, X-linked 96, intellectual disability, X-linked 97, intellectual disability, X-linked 19, intellectual disability, X-linked 89, intellectual disability, X-linked 41, intellectual disability, X-linked 90, intellectual disability, X-linked 92, intellectual disability, X-linked 88, intellectual disability, X-linked 99, intellectual disability, X-linked 100, intellectual disability, X-linked 101, intellectual disability, X-linked 102, intellectual disability, X-linked 61, intellectual disability, X-linked 103, intellectual disability, X-linked 104, intellectual disability, X-linked 105, intellectual disability, X-linked 1, methylmalonic acidemia with homocystinuria, type cblX, FRAXE intellectual disability, intellectual disability, X-linked 9, intellectual developmental disorder, X-linked 108, intellectual disability, X-linked 106, intellectual disability, X-linked 107, intellectual developmental disorder, X-linked 110, intellectual developmental disorder, X-linked 111, intellectual developmental disorder, X-linked 112, intellectual developmental disorder, X-linked 113, intellectual developmental disorder, X-linked 114

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

63 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 11 likely pathogenic, 9 benign, 4 pathogenic, 4 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11568	NM_002578.5(PAK3):c.1255C>T (p.Arg419Ter)	PAK3	Pathogenic	no assertion criteria provided
11569	NM_002578.5(PAK3):c.199C>T (p.Arg67Cys)	PAK3	Pathogenic	criteria provided, single submitter
11570	NM_002578.5(PAK3):c.1094C>A (p.Ala365Glu)	PAK3	Pathogenic	criteria provided, single submitter
11571	NM_002578.5(PAK3):c.1337G>C (p.Trp446Ser)	PAK3	Pathogenic	no assertion criteria provided
1172599	NM_002578.5(PAK3):c.1066G>T (p.Glu356Ter)	PAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3376283	NM_002578.5(PAK3):c.1306C>T (p.Arg436Ter)	PAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438299	NM_002578.5(PAK3):c.298C>T (p.Arg100Ter)	PAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1706590	NM_002578.5(PAK3):c.1182del (p.Leu395fs)	PAK3	Likely pathogenic	criteria provided, single submitter
2499617	NM_002578.5(PAK3):c.176-1G>A	PAK3	Likely pathogenic	criteria provided, single submitter
3238768	NM_002578.5(PAK3):c.600+1G>C	PAK3	Likely pathogenic	criteria provided, single submitter
3251947	NM_002578.5(PAK3):c.276+1G>T	PAK3	Likely pathogenic	criteria provided, single submitter
3572972	NM_002578.5(PAK3):c.748G>T (p.Glu250Ter)	PAK3	Likely pathogenic	criteria provided, single submitter
3897772	NM_002578.5(PAK3):c.1268T>A (p.Val423Glu)	PAK3	Likely pathogenic	criteria provided, single submitter
4813355	NM_002578.5(PAK3):c.766+3G>T	PAK3	Likely pathogenic	criteria provided, single submitter
4846883	NM_002578.5(PAK3):c.1110+1G>T	PAK3	Likely pathogenic	criteria provided, single submitter
633605	NM_002578.5(PAK3):c.1282T>A (p.Trp428Arg)	PAK3	Likely pathogenic	criteria provided, single submitter
689610	NM_002578.5(PAK3):c.1112G>A (p.Cys371Tyr)	PAK3	Likely pathogenic	no assertion criteria provided
981057	NM_002578.5(PAK3):c.403C>T (p.Gln135Ter)	PAK3	Likely pathogenic	criteria provided, single submitter
914022	NM_002578.5(PAK3):c.-473G>C	LOC130068561	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
11572	NM_002578.5(PAK3):c.276+4A>G	PAK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1632107	NM_002578.5(PAK3):c.447A>T (p.Gly149=)	PAK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
431711	NM_002578.5(PAK3):c.1579A>G (p.Ser527Gly)	PAK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3378374	NM_002578.5(PAK3):c.146G>A (p.Arg49His)	LOC130068562	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696511	NM_001128166.3(PAK3):c.-30G>C	PAK3	Uncertain significance	criteria provided, single submitter
1699201	NM_002578.5(PAK3):c.1004G>A (p.Gly335Asp)	PAK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1802565	NM_002578.5(PAK3):c.25G>A (p.Glu9Lys)	PAK3	Uncertain significance	criteria provided, single submitter
2434572	NM_002578.5(PAK3):c.490C>T (p.Pro164Ser)	PAK3	Uncertain significance	criteria provided, single submitter
2434573	NM_002578.5(PAK3):c.1216T>C (p.Phe406Leu)	PAK3	Uncertain significance	criteria provided, single submitter
2434574	NM_002578.5(PAK3):c.233A>G (p.His78Arg)	PAK3	Uncertain significance	criteria provided, single submitter
289750	NM_002578.5(PAK3):c.786G>A (p.Gly262=)	PAK3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
PAK3	Definitive	X-linked	intellectual disability, X-linked 30	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAK3	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAK3	HGNC:8592	ENSG00000077264	O75914	Serine/threonine-protein kinase PAK 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAK3	Serine/threonine-protein kinase PAK 3	Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation.

Protein-family classification

Druggable: 1 · 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	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAK3	Kinase	yes	2.7.11.1	CRIB_dom, Prot_kinase_dom, Ser/Thr_kinase_AS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAK3	214	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAK3	1,870

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAK3	O75914	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 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
CD28 dependent Vav1 pathway	1	878.5×	0.004	PAK3
Activation of RAC1	1	815.7×	0.004	PAK3
Sema3A PAK dependent Axon repulsion	1	671.8×	0.004	PAK3
Ephrin signaling	1	571.0×	0.004	PAK3
RHO GTPases activate PAKs	1	543.8×	0.004	PAK3
CD209 (DC-SIGN) signaling	1	519.1×	0.004	PAK3
VEGFR2 mediated vascular permeability	1	407.9×	0.005	PAK3
Generation of second messenger molecules	1	346.1×	0.005	PAK3
RHOU GTPase cycle	1	278.5×	0.005	PAK3
RHOJ GTPase cycle	1	200.3×	0.006	PAK3
MAPK6/MAPK4 signaling	1	135.9×	0.009	PAK3
CDC42 GTPase cycle	1	72.3×	0.015	PAK3
RAC1 GTPase cycle	1	61.1×	0.016	PAK3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of axonogenesis	1	887.0×	0.005	PAK3
dendritic spine morphogenesis	1	887.0×	0.005	PAK3
stimulatory C-type lectin receptor signaling pathway	1	732.7×	0.005	PAK3
regulation of actin filament polymerization	1	581.1×	0.005	PAK3
regulation of postsynapse organization	1	526.6×	0.005	PAK3
regulation of MAPK cascade	1	455.5×	0.005	PAK3
dendrite development	1	391.9×	0.005	PAK3
ephrin receptor signaling pathway	1	343.9×	0.005	PAK3
synapse organization	1	280.9×	0.006	PAK3
cellular response to starvation	1	193.7×	0.007	PAK3
axonogenesis	1	160.5×	0.007	PAK3
regulation of actin cytoskeleton organization	1	157.5×	0.007	PAK3
cell migration	1	61.5×	0.018	PAK3
intracellular signal transduction	1	38.1×	0.026	PAK3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
PAK3	BOSUTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAK3	17	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BOSUTINIB	4	PAK3
NINTEDANIB	4	PAK3
SUNITINIB	4	PAK3
QUIZARTINIB	4	PAK3
MIDOSTAURIN	4	PAK3
ENZASTAURIN	3	PAK3
DOVITINIB	3	PAK3
LESTAURTINIB	3	PAK3
FORETINIB	2	PAK3
SU-014813	2	PAK3
R-406	2	PAK3
RAF-265	2	PAK3
TOZASERTIB	2	PAK3
KW-2449	1	PAK3
BMS-387032	1	PAK3
PF-03758309	1	PAK3
AST-487	1	PAK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PAK3	240	Binding:240

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAK3	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
PAK3	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

17 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)
BOSUTINIB	4	PAK3
NINTEDANIB	4	PAK3
SUNITINIB	4	PAK3
QUIZARTINIB	4	PAK3
MIDOSTAURIN	4	PAK3
ENZASTAURIN	3	PAK3
DOVITINIB	3	PAK3
LESTAURTINIB	3	PAK3
FORETINIB	2	PAK3
SU-014813	2	PAK3
R-406	2	PAK3
RAF-265	2	PAK3
TOZASERTIB	2	PAK3
KW-2449	1	PAK3
BMS-387032	1	PAK3
PF-03758309	1	PAK3
AST-487	1	PAK3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PAK3
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.