Intellectual disability, autosomal dominant 52

Summary

Intellectual disability, autosomal dominant 52 (MONDO:0030918) is a disease caused by ASH1L (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ASH1L (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 222

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 52
Mondo ID	MONDO:0030918
EFO	EFO:0009152
OMIM	617796
DOID	DOID:0080231
UMLS	C4540478
MedGen	1615839
GARD	0016472
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 52 · intellectual disability, autosomal dominant 52 · mental retardation, autosomal dominant 52 · MRD52

Data availability: 222 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 › autosomal dominant non-syndromic intellectual disability › intellectual disability, autosomal dominant 52

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 53, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual disability, autosomal dominant 56, 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

222 retrieved; paginated sample, class counts are floors:

140 uncertain significance, 26 pathogenic, 25 likely pathogenic, 11 conflicting classifications of pathogenicity, 5 benign, 5 pathogenic/likely pathogenic, 4 likely benign, 3 benign/likely benign, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1047928	NM_018489.3(ASH1L):c.1013C>A (p.Ser338Ter)	ASH1L	Pathogenic	no assertion criteria provided
1285512	NM_018489.3(ASH1L):c.3838C>T (p.Arg1280Ter)	ASH1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1677665	NM_018489.3(ASH1L):c.2134dup (p.Arg712fs)	ASH1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1706432	NM_018489.3(ASH1L):c.7603C>T (p.Arg2535Ter)	ASH1L	Pathogenic	criteria provided, multiple submitters, no conflicts
1710352	NM_018489.3(ASH1L):c.491del (p.Arg164fs)	ASH1L	Pathogenic	criteria provided, single submitter
2573017	NM_018489.3(ASH1L):c.5325C>A (p.Cys1775Ter)	ASH1L	Pathogenic	criteria provided, single submitter
2582343	NM_018489.3(ASH1L):c.6640C>T (p.Arg2214Ter)	ASH1L	Pathogenic	criteria provided, single submitter
2626868	NM_018489.3(ASH1L):c.5569_5585del (p.Pro1857fs)	ASH1L	Pathogenic	criteria provided, single submitter
2627116	NM_018489.3(ASH1L):c.1959del (p.Lys653fs)	ASH1L	Pathogenic	criteria provided, single submitter
3254699	NM_018489.3(ASH1L):c.2966_2969del (p.Met989fs)	ASH1L	Pathogenic	criteria provided, single submitter
3254705	NM_018489.3(ASH1L):c.7021dup (p.Gln2341fs)	ASH1L	Pathogenic	criteria provided, single submitter
3254958	NM_018489.3(ASH1L):c.3937C>T (p.Arg1313Ter)	ASH1L	Pathogenic	criteria provided, single submitter
3370481	NM_018489.3(ASH1L):c.3916C>T (p.Arg1306Ter)	ASH1L	Pathogenic	criteria provided, single submitter
3382380	NM_018489.3(ASH1L):c.7189C>T (p.Arg2397Ter)	ASH1L	Pathogenic	criteria provided, single submitter
3900409	NM_018489.3(ASH1L):c.2332C>T (p.Arg778Ter)	ASH1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4075766	NM_018489.3(ASH1L):c.6178-2A>G	ASH1L	Pathogenic	criteria provided, multiple submitters, no conflicts
4279022	NM_018489.3(ASH1L):c.3828del (p.Gln1278fs)	ASH1L	Pathogenic	criteria provided, single submitter
4293820	NM_018489.3(ASH1L):c.4039_4043del (p.Lys1347fs)	ASH1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4294313	NM_018489.3(ASH1L):c.6267del (p.Thr2090fs)	ASH1L	Pathogenic	criteria provided, single submitter
446511	NM_018489.3(ASH1L):c.2170G>T (p.Ala724Ser)	ASH1L	Pathogenic	no assertion criteria provided
446512	NM_018489.3(ASH1L):c.6238G>A (p.Val2080Ile)	ASH1L	Pathogenic	no assertion criteria provided
446513	NM_018489.3(ASH1L):c.8854dup (p.Arg2952fs)	ASH1L	Pathogenic	no assertion criteria provided
446515	NM_018489.3(ASH1L):c.7764_7768dup (p.Asp2590fs)	ASH1L	Pathogenic	no assertion criteria provided
446516	NM_018489.3(ASH1L):c.6427G>T (p.Glu2143Ter)	ASH1L	Pathogenic	no assertion criteria provided
446517	NM_018489.3(ASH1L):c.8356G>C (p.Ala2786Pro)	ASH1L	Pathogenic	no assertion criteria provided
4532006	NM_018489.3(ASH1L):c.1091_1101del (p.Val364fs)	ASH1L	Pathogenic	criteria provided, single submitter
4687319	NM_018489.3(ASH1L):c.3576_3577del (p.His1192fs)	ASH1L	Pathogenic	criteria provided, single submitter
4687948	NM_018489.3(ASH1L):c.6103+2T>C	ASH1L	Pathogenic	criteria provided, single submitter
559655	NM_018489.3(ASH1L):c.6803_6804delinsTTCTCA (p.Cys2268fs)	ASH1L	Pathogenic	no assertion criteria provided
625522	NM_018489.3(ASH1L):c.3664_3667del (p.Lys1222fs)	ASH1L	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ASH1L	Strong	Autosomal dominant	intellectual disability, autosomal dominant 52	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASH1L	Orphanet:178469	Autosomal dominant 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
ASH1L	HGNC:19088	ENSG00000116539	Q9NR48	Histone-lysine N-methyltransferase ASH1L	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASH1L	Histone-lysine N-methyltransferase ASH1L	Histone methyltransferase specifically trimethylating ‘Lys-36’ of histone H3 forming H3K36me3.

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASH1L	Transcription factor	no	2.1.1.357	BAH_dom, SET_dom, Bromodomain

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
cardia of stomach	1
pylorus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASH1L	267	ubiquitous	marker	Brodmann (1909) area 23, pylorus, cardia of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASH1L	2,789

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASH1L	Q9NR48	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
PKMTs methylate histone lysines	1	160.8×	0.014	ASH1L
Chromatin organization	1	81.6×	0.014	ASH1L
Chromatin modifying enzymes	1	72.3×	0.014	ASH1L

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
tarsal gland development	1	16852.0×	5e-04	ASH1L
uterine gland development	1	16852.0×	5e-04	ASH1L
uterus morphogenesis	1	2808.7×	0.002	ASH1L
negative regulation of acute inflammatory response	1	2407.4×	0.002	ASH1L
decidualization	1	674.1×	0.005	ASH1L
negative regulation of MAPK cascade	1	300.9×	0.009	ASH1L
post-embryonic development	1	205.5×	0.010	ASH1L
single fertilization	1	183.2×	0.010	ASH1L
methylation	1	170.2×	0.010	ASH1L
MAPK cascade	1	153.2×	0.010	ASH1L
skeletal system development	1	125.8×	0.011	ASH1L
flagellated sperm motility	1	117.0×	0.011	ASH1L
transcription by RNA polymerase II	1	70.5×	0.017	ASH1L
inflammatory response	1	37.7×	0.030	ASH1L
regulation of DNA-templated transcription	1	31.6×	0.034	ASH1L
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	ASH1L

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
ASH1L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ASH1L	65	Binding:63, ADMET:1, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASH1L	2.1.1.357	[histone H3]-lysine36 N-dimethyltransferase

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	ASH1L

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)
ASH1L	65	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.