Intellectual disability, autosomal dominant 58

Summary

Intellectual disability, autosomal dominant 58 (MONDO:0020847) is a disease caused by SET (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SET (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 49

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 58
Mondo ID	MONDO:0020847
OMIM	618106
DOID	DOID:0061032
UMLS	C4748195
MedGen	1648488
GARD	0016476
Is cancer (heuristic)	no

Also known as: MENTAL RETARDATION, autosomal dominant 58 · MRD58

Data availability: 49 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 58

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 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 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

49 retrieved; paginated sample, class counts are floors:

17 pathogenic, 14 uncertain significance, 13 likely pathogenic, 3 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4538510	NM_003011.4(SET):c.1A>G (p.Met1Val)	LOC130002718	Pathogenic	criteria provided, single submitter
1344907	NM_003011.4(SET):c.458C>A (p.Ser153Ter)	SET	Pathogenic	criteria provided, single submitter
3392539	NM_003011.4(SET):c.442_443del (p.Ser148fs)	SET	Pathogenic	criteria provided, single submitter
4076402	NM_003011.4(SET):c.204dup (p.Gln69fs)	SET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4540565	NM_003011.4(SET):c.106_109del (p.Asp36fs)	SET	Pathogenic	criteria provided, single submitter
4540568	NM_003011.4(SET):c.77_78del (p.Lys26fs)	SET	Pathogenic	criteria provided, single submitter
4540569	NM_003011.4(SET):c.328_332del (p.Val110fs)	SET	Pathogenic	criteria provided, single submitter
4540570	NM_003011.4(SET):c.493-3_504del	SET	Pathogenic	criteria provided, single submitter
4540571	NM_003011.4(SET):c.644dup (p.Asn215fs)	SET	Pathogenic	criteria provided, single submitter
4540572	NM_003011.4(SET):c.639G>A (p.Trp213Ter)	SET	Pathogenic	criteria provided, single submitter
4540573	NM_003011.4(SET):c.729_732del (p.Glu243fs)	SET	Pathogenic	criteria provided, single submitter
4755524	NM_003011.4(SET):c.493-1G>A	SET	Pathogenic	criteria provided, single submitter
521454	NM_003011.4(SET):c.130_133del (p.Arg44fs)	SET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560206	NM_003011.4(SET):c.244T>G (p.Trp82Gly)	SET	Pathogenic/Likely pathogenic	no assertion criteria provided
560208	NM_003011.4(SET):c.650_651dup (p.Gln218fs)	SET	Pathogenic	no assertion criteria provided
560209	NM_003011.4(SET):c.660_662del (p.Tyr220_Leu221delinsTer)	SET	Pathogenic	criteria provided, single submitter
807681	NM_003011.4(SET):c.418_419del (p.Ser140fs)	SET	Pathogenic	criteria provided, single submitter
817338	NM_003011.4(SET):c.78_81del (p.Lys26fs)	SET	Pathogenic	criteria provided, single submitter
860686	NM_003011.4(SET):c.663+5G>C	SET	Pathogenic	criteria provided, multiple submitters, no conflicts
1707481	NM_001287737.2(SETSIP):c.648G>A (p.Glu216=)	SETSIP	Pathogenic	criteria provided, single submitter
4819993	NM_001122821.2(SET):c.3G>C (p.Met1Ile)	DYNC2I2	Likely pathogenic	no assertion criteria provided
2500283	NM_003011.4(SET):c.219del (p.Glu73fs)	SET	Likely pathogenic	criteria provided, single submitter
2505260	NM_003011.4(SET):c.138dup (p.Glu47Ter)	SET	Likely pathogenic	criteria provided, single submitter
3254904	NM_003011.4(SET):c.103_104del (p.His34_Ile35insTer)	SET	Likely pathogenic	criteria provided, single submitter
4077497	NM_003011.4(SET):c.193C>T (p.Gln65Ter)	SET	Likely pathogenic	criteria provided, single submitter
4540567	NM_003011.4(SET):c.314A>G (p.His105Arg)	SET	Likely pathogenic	criteria provided, single submitter
4819992	NM_003011.4(SET):c.707A>G (p.Asp236Gly)	SET	Likely pathogenic	no assertion criteria provided
4819995	NM_003011.4(SET):c.493-3T>A	SET	Likely pathogenic	no assertion criteria provided
4819996	NM_003011.4(SET):c.420_421del (p.Lys141fs)	SET	Likely pathogenic	no assertion criteria provided
4819997	NM_003011.4(SET):c.378+1G>C	SET	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
SET	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 58	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SET	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SET	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
DYNC2I2	Orphanet:474	Jeune syndrome
DYNC2I2	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SET	HGNC:10760	ENSG00000119335	Q01105	Protein SET	gencc,clinvar
DYNC2I2	HGNC:28296	ENSG00000119333	Q96EX3	Cytoplasmic dynein 2 intermediate chain 2	clinvar
SETSIP	HGNC:42937	ENSG00000230667	P0DME0	Protein SETSIP	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SET	Protein SET	Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning.
DYNC2I2	Cytoplasmic dynein 2 intermediate chain 2	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the i…
SETSIP	Protein SETSIP	Plays a role as a transcriptional activator involved in the early stage of somatic cell reprogramming.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SET	Other/Unknown	no		NAP, NAP-like_sf
DYNC2I2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
SETSIP	Other/Unknown	no		NAP, NAP-like_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
endometrium epithelium	1
ganglionic eminence	1
apex of heart	1
pancreatic ductal cell	1
right uterine tube	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SET	295	ubiquitous	marker	ganglionic eminence, endometrium epithelium, calcaneal tendon
DYNC2I2	238	ubiquitous	marker	right uterine tube, pancreatic ductal cell, apex of heart
SETSIP	28		marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SET	2,822
DYNC2I2	1,099
SETSIP	520

Intra-cohort edges

A	B	Sources
SET	SETSIP	biogrid_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC2I2	Q96EX3	4
SET	Q01105	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SETSIP	P0DME0	78.97

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 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
HuR (ELAVL1) binds and stabilizes mRNA	1	634.4×	0.012	SET
Regulation of mRNA stability by proteins that bind AU-rich elements	1	380.7×	0.012	SET
Mitotic Prophase	1	184.2×	0.016	SET
Intraflagellar transport	1	100.2×	0.022	DYNC2I2
Condensation of Prophase Chromosomes	1	78.2×	0.023	SET
M Phase	1	33.0×	0.045	SET
Cell Cycle, Mitotic	1	24.1×	0.053	SET
Metabolism of RNA	1	20.8×	0.053	SET
Cell Cycle	1	18.0×	0.055	SET

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nucleosome assembly	2	93.6×	0.002	SET, SETSIP
intraciliary retrograde transport	1	374.5×	0.009	DYNC2I2
endothelial cell differentiation	1	374.5×	0.009	SETSIP
nucleosome disassembly	1	267.5×	0.009	SET
intraciliary transport	1	187.2×	0.011	DYNC2I2
DNA replication	1	55.1×	0.030	SET
negative regulation of neuron apoptotic process	1	37.0×	0.038	SET
cilium assembly	1	24.5×	0.050	DYNC2I2
negative regulation of DNA-templated transcription	1	10.5×	0.102	SET
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	SETSIP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SET	1	2
DYNC2I2	0	0
SETSIP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SET	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
MOLIBRESIB	2	SET

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	SET
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	DYNC2I2, SETSIP

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)
DYNC2I2	0	—
SETSIP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.