intellectual disability, X-linked 41

Summary

intellectual disability, X-linked 41 (MONDO:0010451) is a disease caused by GDI1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: GDI1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 41
Mondo ID	MONDO:0010451
OMIM	300849
DOID	DOID:0112058
UMLS	C3887939
MedGen	854647
GARD	0022689
Is cancer (heuristic)	no

Also known as: GDI1 non-syndromic X-linked intellectual disability · intellectual developmental disorder, X-linked 41, X-linked dominant · intellectual disability, X-linked 41 · intellectual disability, X-linked type 41 · mental retardation, X-linked 41 · mental retardation, X-linked 48 · mental retardation, X-linked type 41 · MRX41 · non-syndromic X-linked intellectual disability caused by mutation in GDI1

Data availability: 29 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 41

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 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 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

29 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 7 pathogenic, 4 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3370389	GRCh38/hg38 Xq28(chrX:154348522-154594454)x3	ATP6AP1	Pathogenic	no assertion criteria provided
11627	NM_001493.3(GDI1):c.208C>T (p.Arg70Ter)	GDI1	Pathogenic	no assertion criteria provided
11628	NM_001493.3(GDI1):c.1268G>C (p.Arg423Pro)	GDI1	Pathogenic	no assertion criteria provided
29933	NM_001493.3(GDI1):c.1186_1187del (p.Ser396fs)	GDI1	Pathogenic	no assertion criteria provided
3237495	NM_001493.3(GDI1):c.1088_1089insT (p.Glu363fs)	GDI1	Pathogenic	criteria provided, single submitter
975399	NM_001493.3(GDI1):c.1060_1064del (p.Ser354fs)	GDI1	Pathogenic	no assertion criteria provided
976430	NM_001493.3(GDI1):c.1173_1174insACATGAT (p.Asp392delinsThrTer)	GDI1	Pathogenic	criteria provided, single submitter
1333612	NM_001493.3(GDI1):c.45+1G>A	GDI1	Likely pathogenic	criteria provided, single submitter
1683290	NM_001493.3(GDI1):c.706C>T (p.Gln236Ter)	GDI1	Likely pathogenic	criteria provided, single submitter
1705314	NM_001493.3(GDI1):c.706del (p.Gln236fs)	GDI1	Likely pathogenic	criteria provided, single submitter
976035	NM_001493.3(GDI1):c.788del (p.Gly263fs)	GDI1	Likely pathogenic	criteria provided, single submitter
3598193	NM_001493.3(GDI1):c.1078A>G (p.Thr360Ala)	GDI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435315	NM_001493.3(GDI1):c.193T>A (p.Ser65Thr)	GDI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
11626	NM_001493.3(GDI1):c.275T>C (p.Leu92Pro)	GDI1	Uncertain significance	criteria provided, single submitter
1683576	NM_001493.3(GDI1):c.295T>C (p.Tyr99His)	GDI1	Uncertain significance	criteria provided, single submitter
2432100	NM_001493.3(GDI1):c.518G>A (p.Arg173Gln)	GDI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432101	NM_001493.3(GDI1):c.517C>T (p.Arg173Trp)	GDI1	Uncertain significance	criteria provided, single submitter
2578425	NM_001493.3(GDI1):c.335A>G (p.Lys112Arg)	GDI1	Uncertain significance	criteria provided, single submitter
3340711	NM_001493.3(GDI1):c.359C>T (p.Pro120Leu)	GDI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3381170	NM_001493.3(GDI1):c.494C>G (p.Thr165Ser)	GDI1	Uncertain significance	criteria provided, single submitter
3382388	NM_001493.3(GDI1):c.919C>T (p.Pro307Ser)	GDI1	Uncertain significance	criteria provided, single submitter
3893113	NM_001493.3(GDI1):c.907A>G (p.Ile303Val)	GDI1	Uncertain significance	criteria provided, single submitter
4078765	NM_001493.3(GDI1):c.928A>G (p.Asn310Asp)	GDI1	Uncertain significance	criteria provided, single submitter
4078766	NM_001493.3(GDI1):c.388+10G>A	GDI1	Uncertain significance	criteria provided, single submitter
4082026	NM_001493.3(GDI1):c.396G>A (p.Met132Ile)	GDI1	Uncertain significance	no assertion criteria provided
423705	NM_001493.3(GDI1):c.1283C>T (p.Ala428Val)	GDI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4537361	NM_001493.3(GDI1):c.866A>G (p.Asp289Gly)	GDI1	Uncertain significance	criteria provided, single submitter
129149	NM_001493.3(GDI1):c.219T>C (p.Asn73=)	GDI1	Benign	criteria provided, multiple submitters, no conflicts
129150	NM_001493.3(GDI1):c.324C>T (p.Ser108=)	GDI1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
GDI1	Strong	X-linked	intellectual disability, X-linked 41	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GDI1	Orphanet:777	X-linked non-syndromic intellectual disability
ATP6AP1	Orphanet:692790	ATP6AP1-CDG

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
GDI1	HGNC:4226	ENSG00000203879	P31150	Rab GDP dissociation inhibitor alpha	gencc,clinvar
ATP6AP1	HGNC:868	ENSG00000071553	Q15904	V-type proton ATPase subunit S1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDI1	Rab GDP dissociation inhibitor alpha	Regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them.
ATP6AP1	V-type proton ATPase subunit S1	Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles.

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)
GDI1	Other/Unknown	no		RabGDI, GDP_dissociation_inhibitor, FAD/NAD-bd_sf
ATP6AP1	Other/Unknown	no		Ac45_acc_su, VAS1_LD, VAS1/VOA1_TM

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
Brodmann (1909) area 10	1
endometrium epithelium	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDI1	294	ubiquitous	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
ATP6AP1	291	ubiquitous	marker	endometrium epithelium, Brodmann (1909) area 10, paraflocculus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GDI1	2,331
ATP6AP1	1,759

Intra-cohort edges

A	B	Sources
ATP6AP1	GDI1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6AP1	Q15904	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GDI1	P31150	93.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Insulin receptor recycling	1	190.3×	0.014	ATP6AP1
Transferrin endocytosis and recycling	1	184.2×	0.014	ATP6AP1
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.026	GDI1
Ion channel transport	1	48.0×	0.026	ATP6AP1
RHOA GTPase cycle	1	37.3×	0.027	ATP6AP1

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
negative regulation of protein localization	1	2808.7×	0.003	GDI1
positive regulation of toll-like receptor signaling pathway	1	2106.5×	0.003	GDI1
obsolete regulation of cellular pH	1	1685.2×	0.003	ATP6AP1
endosome to plasma membrane protein transport	1	1685.2×	0.003	ATP6AP1
negative regulation of protein targeting to membrane	1	1404.3×	0.003	GDI1
osteoclast development	1	1053.2×	0.003	ATP6AP1
cellular response to increased oxygen levels	1	1053.2×	0.003	ATP6AP1
Golgi lumen acidification	1	842.6×	0.003	ATP6AP1
negative regulation of axonogenesis	1	648.1×	0.003	GDI1
endosomal lumen acidification	1	601.9×	0.003	ATP6AP1
intracellular pH reduction	1	601.9×	0.003	ATP6AP1
Rab protein signal transduction	1	495.6×	0.004	GDI1
synaptic vesicle lumen acidification	1	468.1×	0.004	ATP6AP1
vacuolar acidification	1	366.4×	0.004	ATP6AP1
lysosomal lumen acidification	1	337.0×	0.004	ATP6AP1
positive regulation of axon extension	1	255.3×	0.005	GDI1
response to calcium ion	1	159.0×	0.008	GDI1
proton transmembrane transport	1	156.0×	0.008	ATP6AP1
intracellular iron ion homeostasis	1	122.1×	0.009	ATP6AP1
vesicle-mediated transport	1	48.1×	0.023	GDI1
protein transport	1	21.9×	0.047	GDI1
signal transduction	1	8.0×	0.121	GDI1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
GDI1	0	0
ATP6AP1	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
ATP6AP1	7	Binding:7
GDI1	1	Binding:1

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	GDI1, ATP6AP1

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)
GDI1	1	—
ATP6AP1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.