Intellectual disability, autosomal dominant 56

Summary

Intellectual disability, autosomal dominant 56 (MONDO:0030922) is a disease caused by CLTC (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CLTC (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 111

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 56
Mondo ID	MONDO:0030922
OMIM	617854
DOID	DOID:0080226
UMLS	C4693389
MedGen	1638835
GARD	0013524
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 56 · CLTC-related disorder · CLTC-related ID · CLTC-related intellectual disability · intellectual disability, autosomal dominant 56 · mental retardation, autosomal dominant 56 · MRD56

Data availability: 111 ClinVar variants · 5 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 › autosomal dominant non-syndromic intellectual disability › intellectual disability, autosomal dominant 56

Related subtypes (25): intellectual disability, autosomal dominant 22, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, intellectual disability, autosomal dominant 33, intellectual disability, autosomal dominant 34, intellectual disability, autosomal dominant 41, intellectual disability, autosomal dominant 43, intellectual disability, autosomal dominant 58, intellectual disability, autosomal dominant 45, intellectual disability, autosomal dominant 46, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, intellectual disability, autosomal dominant 52, intellectual disability, autosomal dominant 53, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual developmental disorder 61, intellectual developmental disorder 59, intellectual developmental disorder 60 with seizures, intellectual developmental disorder 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, Coffin-Siris syndrome 6, intellectual disability, autosomal dominant 57, intellectual developmental disorder, autosomal dominant 73

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

111 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 29 pathogenic, 29 likely pathogenic, 6 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 3 benign, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029302	NM_004859.4(CLTC):c.4602C>G (p.Tyr1534Ter)	CLTC	Pathogenic	criteria provided, single submitter
1254197	NM_004859.4(CLTC):c.4691_4692del (p.Glu1564fs)	CLTC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1283912	NM_004859.4(CLTC):c.2646_2649del (p.Ile882_Tyr883insTer)	CLTC	Pathogenic	criteria provided, single submitter
1320245	NM_004859.4(CLTC):c.4722C>G (p.Tyr1574Ter)	CLTC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1527908	NM_004859.4(CLTC):c.3470T>A (p.Leu1157Ter)	CLTC	Pathogenic	criteria provided, single submitter
1527930	NM_004859.4(CLTC):c.3766-13_3766-5del	CLTC	Pathogenic	criteria provided, single submitter
1685641	NM_004859.4(CLTC):c.2023A>G (p.Ile675Val)	CLTC	Pathogenic	criteria provided, single submitter
1685642	NM_004859.4(CLTC):c.3765+1G>A	CLTC	Pathogenic	criteria provided, single submitter
1895389	NM_004859.4(CLTC):c.1898T>A (p.Leu633Ter)	CLTC	Pathogenic	criteria provided, single submitter
1992348	NM_004859.4(CLTC):c.2438del (p.Pro813fs)	CLTC	Pathogenic	criteria provided, single submitter
208688	NM_004859.4(CLTC):c.2737_2738dup (p.Asp913fs)	CLTC	Pathogenic	criteria provided, single submitter
2573029	NM_004859.4(CLTC):c.1976C>G (p.Ser659Ter)	CLTC	Pathogenic	criteria provided, single submitter
2626759	NM_004859.4(CLTC):c.3249+1G>C	CLTC	Pathogenic	no assertion criteria provided
2690891	NM_004859.4(CLTC):c.3339dup (p.Ala1114fs)	CLTC	Pathogenic	criteria provided, single submitter
3066041	NM_004859.4(CLTC):c.3049_3050del (p.Val1017fs)	CLTC	Pathogenic	no assertion criteria provided
3066075	NM_004859.4(CLTC):c.4686_4687del (p.Glu1564fs)	CLTC	Pathogenic	no assertion criteria provided
3382699	NM_004859.4(CLTC):c.1647_1653del	CLTC	Pathogenic	criteria provided, single submitter
3382723	NM_004859.4(CLTC):c.1495C>T (p.Gln499Ter)	CLTC	Pathogenic	criteria provided, single submitter
3777088	NM_004859.4(CLTC):c.4570_4571del (p.Ser1524fs)	CLTC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3778736	NM_004859.4(CLTC):c.4827+1G>T	CLTC	Pathogenic	criteria provided, single submitter
3897858	NM_004859.4(CLTC):c.46C>T (p.Gln16Ter)	CLTC	Pathogenic	criteria provided, single submitter
4082287	NM_004859.4(CLTC):c.3478_3482del (p.Met1159_Ala1160insTer)	CLTC	Pathogenic	criteria provided, single submitter
4293921	NM_004859.4(CLTC):c.3751C>T (p.Arg1251Ter)	CLTC	Pathogenic	criteria provided, single submitter
4294359	NM_004859.4(CLTC):c.4225C>T (p.Gln1409Ter)	CLTC	Pathogenic	criteria provided, single submitter
4531672	NM_004859.4(CLTC):c.2636T>G (p.Leu879Ter)	CLTC	Pathogenic	criteria provided, single submitter
488416	NM_004859.4(CLTC):c.4575dup (p.Glu1526fs)	CLTC	Pathogenic	no assertion criteria provided
488417	NM_004859.4(CLTC):c.977_980del (p.Ser326fs)	CLTC	Pathogenic	no assertion criteria provided
488418	NM_004859.4(CLTC):c.2669C>T (p.Pro890Leu)	CLTC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488419	NM_004859.4(CLTC):c.3140T>C (p.Leu1047Pro)	CLTC	Pathogenic	no assertion criteria provided
488420	NM_004859.4(CLTC):c.4663C>T (p.Gln1555Ter)	CLTC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · 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
CLTC	Strong	Autosomal dominant	intellectual disability, autosomal dominant 56	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLTC	Orphanet:178342	Inflammatory myofibroblastic tumor
CLTC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CLTC	Orphanet:319308	MiT family translocation renal cell carcinoma
CLTC	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
MMP20	Orphanet:100033	Hypomaturation amelogenesis imperfecta

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
CLTC	HGNC:2092	ENSG00000141367	Q00610	Clathrin heavy chain 1	gencc,clinvar
MMP20	HGNC:7167	ENSG00000137674	O60882	Matrix metalloproteinase-20	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLTC	Clathrin heavy chain 1	Clathrin is the major protein of the polyhedral coat of coated pits and vesicles.
MMP20	Matrix metalloproteinase-20	Degrades amelogenin, the major protein component of the enamel matrix and two of the macromolecules characterizing the cartilage extracellular matrix: aggrecan and the cartilage oligomeric matrix protein (COMP).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLTC	Other/Unknown	no		Clathrin_H-chain/VPS_repeat, TPR-like_helical_dom_sf, Clathrin_H-chain_linker_core
MMP20	Protease	yes	3.4.24.B6	Hemopexin-like_dom, Pept_M10_metallopeptidase, Peptidoglycan-bd-like

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
Brodmann (1909) area 46	1
lateral nuclear group of thalamus	1
pons	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLTC	305	ubiquitous	marker	pons, lateral nuclear group of thalamus, Brodmann (1909) area 46
MMP20	56		marker	left testis, testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLTC	5,550
MMP20	503

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLTC	Q00610	10
MMP20	O60882	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. 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
Entry of Influenza Virion into Host Cell via Endocytosis	1	2855.0×	0.008	CLTC
Formation of annular gap junctions	1	519.1×	0.008	CLTC
Gap junction degradation	1	475.8×	0.008	CLTC
ALK mutants bind TKIs	1	475.8×	0.008	CLTC
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	1	439.2×	0.008	CLTC
Retrograde neurotrophin signalling	1	407.9×	0.008	CLTC
WNT5A-dependent internalization of FZD4	1	380.7×	0.008	CLTC
VLDLR internalisation and degradation	1	356.9×	0.008	CLTC
LDL clearance	1	271.9×	0.010	CLTC
Collagen formation	1	228.4×	0.010	MMP20
Lysosome Vesicle Biogenesis	1	163.1×	0.013	CLTC
RHOV GTPase cycle	1	142.8×	0.013	CLTC
RHOU GTPase cycle	1	139.3×	0.013	CLTC
Recycling pathway of L1	1	112.0×	0.014	CLTC
EPH-ephrin mediated repulsion of cells	1	109.8×	0.014	CLTC
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.014	MMP20
Golgi Associated Vesicle Biogenesis	1	100.2×	0.014	CLTC
Collagen degradation	1	87.8×	0.015	MMP20
Signaling by ALK fusions and activated point mutants	1	75.1×	0.017	CLTC
Degradation of the extracellular matrix	1	58.9×	0.020	MMP20
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.022	CLTC
MHC class II antigen presentation	1	44.6×	0.024	CLTC
Clathrin-mediated endocytosis	1	42.6×	0.024	CLTC
Extracellular matrix organization	1	31.6×	0.031	MMP20

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 enamel mineralization	1	2808.7×	0.004	MMP20
clathrin coat disassembly	1	2106.5×	0.004	CLTC
negative regulation of hyaluronan biosynthetic process	1	2106.5×	0.004	CLTC
amyloid-beta clearance by transcytosis	1	1203.7×	0.005	CLTC
transferrin transport	1	766.0×	0.005	CLTC
amelogenesis	1	702.2×	0.005	MMP20
clathrin coat assembly	1	443.5×	0.007	CLTC
regulation of mitotic spindle organization	1	421.3×	0.007	CLTC
negative regulation of protein localization to plasma membrane	1	312.1×	0.008	CLTC
clathrin-dependent endocytosis	1	290.6×	0.008	CLTC
collagen catabolic process	1	195.9×	0.010	MMP20
extracellular matrix disassembly	1	183.2×	0.010	MMP20
receptor internalization	1	162.0×	0.011	CLTC
protein catabolic process	1	118.7×	0.014	MMP20
receptor-mediated endocytosis	1	110.9×	0.014	CLTC
retrograde transport, endosome to Golgi	1	102.8×	0.014	CLTC
mitotic cell cycle	1	66.9×	0.020	CLTC
extracellular matrix organization	1	61.1×	0.020	MMP20
osteoblast differentiation	1	60.6×	0.020	CLTC
autophagy	1	55.1×	0.021	CLTC
intracellular protein transport	1	32.4×	0.034	CLTC
cell division	1	23.1×	0.045	CLTC
proteolysis	1	17.1×	0.058	MMP20

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MMP20	1	3
CLTC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MARIMASTAT	3	MMP20

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CLTC	8	Binding:8
MMP20	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMP20	3.4.24.B6

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

1 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)
MARIMASTAT	3	MMP20

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	1	MMP20
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLTC

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)
CLTC	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.