Intellectual disability, autosomal recessive 18

Summary

Intellectual disability, autosomal recessive 18 (MONDO:0013651) is a disease caused by MED23 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: MED23 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 18
Mondo ID	MONDO:0013651
OMIM	614249
DOID	DOID:0081190
UMLS	C3280265
MedGen	481895
GARD	0022552
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in MED23 · autosomal recessive nonsyndromic intellectual disability-18 · autosomal recessive nonsyndromic mental retardation-18 · intellectual developmental disorder, autosomal recessive 18, with or without epilepsy · intellectual disability, autosomal recessive 18 · intellectual disability, autosomal recessive type 18 · MED23 · MED23 autosomal recessive non-syndromic intellectual disability · mental retardation, autosomal recessive 18 · mental retardation, autosomal recessive type 18 · MRT18

Data availability: 35 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 recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 18

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

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

35 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 7 pathogenic, 5 likely pathogenic, 5 conflicting classifications of pathogenicity, 2 not provided, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032717	NM_004830.4(MED23):c.2832dup (p.Val945fs)	MED23	Pathogenic	criteria provided, single submitter
1327487	NM_004830.4(MED23):c.506A>G (p.Tyr169Cys)	MED23	Pathogenic	no assertion criteria provided
1327489	NM_004830.4(MED23):c.382G>A (p.Gly128Arg)	MED23	Pathogenic	no assertion criteria provided
1327491	NM_004830.4(MED23):c.1919A>G (p.Gln640Arg)	MED23	Pathogenic	no assertion criteria provided
143192	NM_004830.4(MED23):c.3638A>G (p.His1213Arg)	MED23	Pathogenic	no assertion criteria provided
437437	NM_004830.4(MED23):c.670C>G (p.Arg224Gly)	MED23	Pathogenic	criteria provided, single submitter
4813535	NM_004830.4(MED23):c.3983G>C (p.Arg1328Pro)	MED23	Pathogenic	criteria provided, single submitter
620500	NM_004830.4(MED23):c.3353C>G (p.Ser1118Ter)	MED23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029420	NM_004830.4(MED23):c.1181C>T (p.Pro394Leu)	MED23	Likely pathogenic	criteria provided, single submitter
191215	NM_004830.4(MED23):c.479T>C (p.Leu160Pro)	MED23	Likely pathogenic	criteria provided, single submitter
30442	NM_004830.4(MED23):c.1832G>A (p.Arg611Gln)	MED23	Likely pathogenic	criteria provided, single submitter
3382460	NM_004830.4(MED23):c.3145del (p.Tyr1048_Leu1049insTer)	MED23	Likely pathogenic	criteria provided, single submitter
559910	NM_004830.4(MED23):c.2368_2371del (p.Leu790fs)	MED23	Likely pathogenic	criteria provided, single submitter
143193	NM_004830.4(MED23):c.3988C>T (p.Arg1330Ter)	MED23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2442027	NM_004830.4(MED23):c.1078-6T>G	MED23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432201	NM_004830.4(MED23):c.4080G>T (p.Val1360=)	MED23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
489309	NM_004830.4(MED23):c.3939+5G>A	MED23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802270	NM_004830.4(MED23):c.3982C>T (p.Arg1328Cys)	MED23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030847	NM_004830.4(MED23):c.1708T>G (p.Leu570Val)	MED23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032715	NM_004830.4(MED23):c.2176A>G (p.Asn726Asp)	MED23	Uncertain significance	criteria provided, single submitter
1033382	NM_004830.4(MED23):c.3566G>T (p.Arg1189Leu)	MED23	Uncertain significance	criteria provided, single submitter
1033383	NM_004830.4(MED23):c.3980T>G (p.Leu1327Arg)	MED23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1327490	NM_004830.4(MED23):c.539C>A (p.Ala180Asp)	MED23	Uncertain significance	criteria provided, single submitter
1699040	NM_004830.4(MED23):c.2998C>A (p.Arg1000Ser)	MED23	Uncertain significance	criteria provided, single submitter
1801051	NM_004830.4(MED23):c.2528T>C (p.Leu843Pro)	MED23	Uncertain significance	criteria provided, single submitter
211484	NM_004830.4(MED23):c.235C>T (p.Leu79Phe)	MED23	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065162	NM_004830.4(MED23):c.3982C>A (p.Arg1328Ser)	MED23	Uncertain significance	criteria provided, single submitter
3394641	NM_004830.4(MED23):c.2062A>G (p.Ile688Val)	MED23	Uncertain significance	criteria provided, multiple submitters, no conflicts
3773735	NM_004830.4(MED23):c.1957A>G (p.Ile653Val)	MED23	Uncertain significance	criteria provided, single submitter
435850	NM_004830.4(MED23):c.3963A>T (p.Leu1321Phe)	MED23	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
MED23	Strong	Autosomal recessive	intellectual disability, autosomal recessive 18	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED23	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
ARG1	Orphanet:90	Argininemia

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
MED23	HGNC:2372	ENSG00000112282	Q9ULK4	Mediator of RNA polymerase II transcription subunit 23	gencc,clinvar
ARG1	HGNC:663	ENSG00000118520	P05089	Arginase-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED23	Mediator of RNA polymerase II transcription subunit 23	Required for transcriptional activation subsequent to the assembly of the pre-initiation complex.
ARG1	Arginase-1	Key element of the urea cycle converting L-arginine to urea and L-ornithine, which is further metabolized into metabolites proline and polyamides that drive collagen synthesis and bioenergetic pathways critical for cell proliferation, resp…

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED23	Other/Unknown	no		Mediator_Med23
ARG1	Enzyme (other)	yes	3.5.3.1	Ureohydrolase, Arginase, Ureohydrolase_Mn_BS

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
liver	1
penis	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED23	283	ubiquitous	yes	right hemisphere of cerebellum, calcaneal tendon, cerebellar hemisphere
ARG1	194	tissue_specific	marker	right lobe of liver, liver, penis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARG1	4,432
MED23	2,155

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARG1	P05089	60
MED23	Q9ULK4	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. 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
ARG1 variants cause hyperargininemia	1	5710.0×	0.005	ARG1
Urea cycle	1	439.2×	0.030	ARG1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.036	MED23
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.036	MED23
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.036	MED23
RSV-host interactions	1	78.2×	0.036	MED23
Adipogenesis	1	78.2×	0.036	MED23
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.036	MED23
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.036	MED23
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.036	MED23
Metabolism	2	11.6×	0.036	MED23, ARG1
PPARA activates gene expression	1	47.2×	0.046	MED23
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.048	MED23
Epigenetic regulation of gene expression	1	35.7×	0.051	MED23
Metabolism of amino acids and derivatives	1	33.8×	0.051	ARG1
Metabolism of lipids	1	15.8×	0.098	MED23
Viral Infection Pathways	1	15.4×	0.098	MED23
Innate Immune System	1	12.8×	0.107	ARG1
Infectious disease	1	12.4×	0.107	MED23
Neutrophil degranulation	1	11.5×	0.107	ARG1
RNA Polymerase II Transcription	1	11.3×	0.107	MED23
Gene expression (Transcription)	1	8.9×	0.129	MED23
Generic Transcription Pathway	1	7.5×	0.145	MED23
Developmental Biology	1	7.2×	0.145	MED23
Disease	1	6.5×	0.148	MED23
Immune System	1	6.5×	0.148	ARG1

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
positive regulation of neutrophil mediated killing of fungus	1	8426.0×	0.002	ARG1
positive regulation of T cell extravasation	1	4213.0×	0.002	MED23
negative regulation of T-helper 2 cell cytokine production	1	2106.5×	0.003	ARG1
L-arginine catabolic process	1	1404.3×	0.003	ARG1
negative regulation of type II interferon-mediated signaling pathway	1	1053.2×	0.003	ARG1
response to nematode	1	936.2×	0.003	ARG1
urea cycle	1	648.1×	0.004	ARG1
negative regulation of activated T cell proliferation	1	526.6×	0.005	ARG1
defense response to protozoan	1	300.9×	0.007	ARG1
transcription initiation at RNA polymerase II promoter	1	187.2×	0.010	MED23
negative regulation of T cell proliferation	1	165.2×	0.010	ARG1
positive regulation of transcription elongation by RNA polymerase II	1	150.5×	0.010	MED23
RNA polymerase II preinitiation complex assembly	1	135.9×	0.010	MED23
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.010	MED23
adaptive immune response	1	42.1×	0.030	ARG1
positive regulation of gene expression	1	19.4×	0.061	MED23
innate immune response	1	16.8×	0.066	ARG1
regulation of DNA-templated transcription	1	15.8×	0.066	MED23
regulation of transcription by RNA polymerase II	1	5.8×	0.164	MED23

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MED23	PALBOCICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARG1	2	2
MED23	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	MED23
NUMIDARGISTAT	2	ARG1
NOR-NOHA	1	ARG1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ARG1	90	Binding:86, Functional:4
MED23	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ARG1	3.5.3.1	arginase

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

3 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)
PALBOCICLIB	4	MED23
NUMIDARGISTAT	2	ARG1
NOR-NOHA	1	ARG1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MED23
B	Phased (≥1) drug, not yet approved	1	ARG1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.