intellectual disability, X-linked 72

Summary

intellectual disability, X-linked 72 (MONDO:0010289) is a disease caused by RAB39B (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: RAB39B (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 41

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 72
Mondo ID	MONDO:0010289
MeSH	C564547
OMIM	300271
DOID	DOID:0112059
UMLS	C1846038
MedGen	375793
GARD	0022671
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked 72, X-linked recessive · intellectual disability, X-linked 72 · intellectual disability, X-linked type 72 · mental retardation, X-linked 72 · mental retardation, X-linked type 72 · MRX72

Data availability: 41 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 72

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 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 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

41 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 9 benign, 4 pathogenic, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4819213	Single allele	H2AB2	Pathogenic	criteria provided, single submitter
10542	NM_171998.4(RAB39B):c.215+1G>A	RAB39B	Pathogenic	no assertion criteria provided
10543	NM_171998.4(RAB39B):c.21C>A (p.Tyr7Ter)	RAB39B	Pathogenic	no assertion criteria provided
436462	NM_171998.4(RAB39B):c.559G>T (p.Glu187Ter)	RAB39B	Pathogenic	criteria provided, single submitter
1691598	NM_171998.4(RAB39B):c.137dup (p.Ser47fs)	RAB39B	Likely pathogenic	criteria provided, single submitter
3381756	NM_171998.4(RAB39B):c.426TGC[1] (p.Ala144del)	RAB39B	Likely pathogenic	criteria provided, single submitter
368143	NM_171998.4(RAB39B):c.*339T>C	RAB39B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
912927	NM_171998.4(RAB39B):c.*1452T>C	RAB39B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
368148	NM_171998.4(RAB39B):c.-61G>C	LOC130068896	Uncertain significance	criteria provided, single submitter
914413	NM_171998.4(RAB39B):c.-84C>G	LOC130068896	Uncertain significance	criteria provided, single submitter
1679228	NM_171998.4(RAB39B):c.43G>C (p.Gly15Arg)	RAB39B	Uncertain significance	criteria provided, single submitter
3382000	NM_171998.4(RAB39B):c.287C>T (p.Ser96Phe)	RAB39B	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382481	NM_171998.4(RAB39B):c.43G>A (p.Gly15Arg)	RAB39B	Uncertain significance	criteria provided, single submitter
368127	NM_171998.4(RAB39B):c.*2100C>T	RAB39B	Uncertain significance	criteria provided, single submitter
368130	NM_171998.4(RAB39B):c.*1935G>A	RAB39B	Uncertain significance	criteria provided, single submitter
368132	NM_171998.4(RAB39B):c.*1728A>G	RAB39B	Uncertain significance	criteria provided, single submitter
368136	NM_171998.4(RAB39B):c.*1428T>G	RAB39B	Uncertain significance	criteria provided, single submitter
368142	NM_171998.4(RAB39B):c.*485T>G	RAB39B	Uncertain significance	criteria provided, single submitter
368146	NM_171998.4(RAB39B):c.*65A>G	RAB39B	Uncertain significance	criteria provided, single submitter
368147	NM_171998.4(RAB39B):c.273T>C (p.Ile91=)	RAB39B	Uncertain significance	criteria provided, single submitter
3764754	NM_171998.4(RAB39B):c.511A>G (p.Ile171Val)	RAB39B	Uncertain significance	criteria provided, single submitter
3775166	NM_171998.4(RAB39B):c.402_403del (p.Arg135fs)	RAB39B	Uncertain significance	criteria provided, single submitter
3901193	NM_171998.4(RAB39B):c.199G>T (p.Gly67Cys)	RAB39B	Uncertain significance	criteria provided, single submitter
913297	NM_171998.4(RAB39B):c.*588A>G	RAB39B	Uncertain significance	criteria provided, single submitter
913298	NM_171998.4(RAB39B):c.*428C>T	RAB39B	Uncertain significance	criteria provided, single submitter
914412	NM_171998.4(RAB39B):c.-62C>A	RAB39B	Uncertain significance	criteria provided, single submitter
914872	NM_171998.4(RAB39B):c.*2551T>C	RAB39B	Uncertain significance	criteria provided, single submitter
914873	NM_171998.4(RAB39B):c.*2366G>A	RAB39B	Uncertain significance	criteria provided, single submitter
930800	NM_171998.4(RAB39B):c.349G>T (p.Val117Leu)	RAB39B	Uncertain significance	criteria provided, single submitter
931638	NM_171998.4(RAB39B):c.64T>G (p.Ser22Ala)	RAB39B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
RAB39B	Definitive	X-linked	intellectual disability, X-linked 72	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAB39B	Orphanet:2379	Early-onset parkinsonism-intellectual disability syndrome
RAB39B	Orphanet:777	X-linked non-syndromic intellectual disability

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
RAB39B	HGNC:16499	ENSG00000155961	Q96DA2	Ras-related protein Rab-39B	gencc,clinvar
H2AB2	HGNC:18298	ENSG00000277858	P0C5Z0	Histone H2A-Bbd type 2/3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB39B	Ras-related protein Rab-39B	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
H2AB2	Histone H2A-Bbd type 2/3	Atypical histone H2A which can replace conventional H2A in some nucleosomes and is associated with active transcription and mRNA processing.

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)
RAB39B	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
H2AB2	Other/Unknown	no		Histone_H2A, Histone-fold

Expression context

Cohort genes with no expression data: 0.

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
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
left testis	1
primordial germ cell in gonad	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB39B	172	broad	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
H2AB2	113		yes	primordial germ cell in gonad, left testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAB39B	1,269
H2AB2	1,174

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
H2AB2	P0C5Z0	4
RAB39B	Q96DA2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
RAB geranylgeranylation	1	173.0×	0.008	RAB39B
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.008	RAB39B

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
Rab protein signal transduction	1	495.6×	0.018	RAB39B
synapse organization	1	140.4×	0.019	RAB39B
heterochromatin formation	1	127.7×	0.019	H2AB2
regulation of autophagy	1	120.4×	0.019	RAB39B
nucleosome assembly	1	70.2×	0.026	H2AB2
autophagy	1	55.1×	0.027	RAB39B
vesicle-mediated transport	1	48.1×	0.027	RAB39B
mRNA processing	1	39.4×	0.028	H2AB2
protein transport	1	21.9×	0.045	RAB39B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAB39B	0	0
H2AB2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	RAB39B, H2AB2

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)
RAB39B	0	—
H2AB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.