intellectual disability, X-linked 46

Summary

intellectual disability, X-linked 46 (MONDO:0010326) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 46
Mondo ID	MONDO:0010326
MeSH	C564513
OMIM	300436
DOID	DOID:0112055
UMLS	C1845526
MedGen	337255
GARD	0022677
Is cancer (heuristic)	no

Also known as: intellectual disability, X-linked 46 · intellectual disability, X-linked type 46 · mental retardation, X-linked 46 · mental retardation, X-linked 46, X-linked recessive · mental retardation, X-linked type 46 · MRX46

Data availability: 6 ClinVar variants · 3 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 46

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 77, intellectual disability, X-linked 45, intellectual disability, X-linked 84, intellectual disability, X-linked 82, intellectual disability, X-linked 30, 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

6 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
210251	NM_004840.3(ARHGEF6):c.169T>C (p.Cys57Arg)	ARHGEF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028304	NM_004840.3(ARHGEF6):c.1769G>A (p.Ser590Asn)	ARHGEF6	Uncertain significance	criteria provided, single submitter
1028305	NM_004840.3(ARHGEF6):c.2024G>T (p.Gly675Val)	ARHGEF6	Uncertain significance	criteria provided, multiple submitters, no conflicts
451586	NM_004840.3(ARHGEF6):c.1943A>G (p.Lys648Arg)	ARHGEF6	Uncertain significance	criteria provided, multiple submitters, no conflicts
128447	NM_004840.3(ARHGEF6):c.362G>A (p.Arg121His)	ARHGEF6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
367947	NM_004840.3(ARHGEF6):c.166-11T>C	ARHGEF6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
ARHGEF6	Supportive	X-linked	non-syndromic X-linked intellectual disability	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARHGEF6	Orphanet:777	X-linked non-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
ARHGEF6	HGNC:685	ENSG00000129675	Q15052	Rho guanine nucleotide exchange factor 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARHGEF6	Rho guanine nucleotide exchange factor 6	Acts as a RAC1 guanine nucleotide exchange factor (GEF).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARHGEF6	Scaffold/PPI	no		DH_dom, SH3_domain, CH_dom

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
biceps brachii	1
medial globus pallidus	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARHGEF6	289	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARHGEF6	1,668

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARHGEF6	Q15052	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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
G-protein beta:gamma signalling	1	1903.3×	0.007	ARHGEF6
Regulation of cytoskeletal remodeling and cell spreading by IPP complex components	1	1427.5×	0.007	ARHGEF6
Cell-extracellular matrix interactions	1	671.8×	0.009	ARHGEF6
G beta:gamma signalling through CDC42	1	571.0×	0.009	ARHGEF6
RHOU GTPase cycle	1	278.5×	0.012	ARHGEF6
Cell death signalling via NRAGE, NRIF and NADE	1	219.6×	0.012	ARHGEF6
p75 NTR receptor-mediated signalling	1	187.2×	0.012	ARHGEF6
Cell junction organization	1	187.2×	0.012	ARHGEF6
NRAGE signals death through JNK	1	184.2×	0.012	ARHGEF6
Death Receptor Signaling	1	139.3×	0.012	ARHGEF6
Cell-Cell communication	1	137.6×	0.012	ARHGEF6
G alpha (12/13) signalling events	1	137.6×	0.012	ARHGEF6
CDC42 GTPase cycle	1	72.3×	0.021	ARHGEF6
RAC1 GTPase cycle	1	61.1×	0.022	ARHGEF6
RHO GTPase cycle	1	60.1×	0.022	ARHGEF6
GPCR downstream signalling	1	43.4×	0.029	ARHGEF6
Signaling by GPCR	1	40.1×	0.029	ARHGEF6
Signaling by Rho GTPases	1	34.2×	0.031	ARHGEF6
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.031	ARHGEF6
Signal Transduction	1	10.2×	0.098	ARHGEF6

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
lamellipodium assembly	1	443.5×	0.006	ARHGEF6
JNK cascade	1	271.8×	0.006	ARHGEF6
apoptotic process	1	28.7×	0.035	ARHGEF6

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARHGEF6	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
ARHGEF6	6	Binding:6

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

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	1	ARHGEF6

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)
ARHGEF6	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.