intellectual disability, X-linked 21

Summary

intellectual disability, X-linked 21 (MONDO:0010256) is a disease caused by IL1RAPL1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: IL1RAPL1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 65

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 21
Mondo ID	MONDO:0010256
OMIM	300143
DOID	DOID:0112022
UMLS	C5551510
MedGen	1790509
GARD	0022669
Is cancer (heuristic)	no

Also known as: IL1RAPL1 non-syndromic X-linked intellectual disability · intellectual developmental disorder, X-linked 21, X-linked recessive · intellectual disability, X-linked 21 · intellectual disability, X-linked type 21 · mental retardation, X-linked 21 · mental retardation, X-linked 34 · mental retardation, X-linked type 21 · MRX21 · non-syndromic X-linked intellectual disability caused by mutation in IL1RAPL1

Data availability: 65 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 › non-syndromic X-linked intellectual disability › intellectual disability, X-linked 21

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 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 41, 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

65 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 12 likely pathogenic, 8 benign/likely benign, 7 pathogenic, 7 benign, 5 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
11480	NM_014271.4(IL1RAPL1):c.1377C>A (p.Tyr459Ter)	IL1RAPL1	Pathogenic	no assertion criteria provided
11482	NG_008292.2:g.(?707879)(1040749_?)del	IL1RAPL1	Pathogenic	no assertion criteria provided
1334575	NM_014271.4(IL1RAPL1):c.148C>T (p.Arg50Ter)	IL1RAPL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29944	NG_008292.1:g.700375-?_1335033+?del	IL1RAPL1	Pathogenic	no assertion criteria provided
4532187	NM_014271.4(IL1RAPL1):c.1027C>T (p.Arg343Ter)	IL1RAPL1	Pathogenic	criteria provided, single submitter
620044	NM_014271.4(IL1RAPL1):c.1191_1201+6del	IL1RAPL1	Pathogenic	criteria provided, single submitter
620223	NM_014271.4(IL1RAPL1):c.1054C>T (p.Arg352Ter)	IL1RAPL1	Pathogenic	criteria provided, multiple submitters, no conflicts
813316	GRCh37/hg19 Xp21.2(chrX:29686547-29686621)	IL1RAPL1	Pathogenic	criteria provided, single submitter
11481	NM_014271.4(IL1RAPL1):c.1460G>A (p.Trp487Ter)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
1174094	NM_014271.4(IL1RAPL1):c.1891_1897del (p.Asp631fs)	IL1RAPL1	Likely pathogenic	no assertion criteria provided
1320221	NM_014271.4(IL1RAPL1):c.1075del (p.Glu359fs)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
1321320	NM_014271.4(IL1RAPL1):c.1227dup (p.Ser410fs)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
2572320	NM_014271.4(IL1RAPL1):c.366_379delinsGTAACAAAG (p.Asn122_Met127delinsLysTer)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
3251939	NM_014271.4(IL1RAPL1):c.82+2T>C	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
3253623	NM_014271.4(IL1RAPL1):c.1743_1744del (p.Phe581fs)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
3598251	NM_014271.4(IL1RAPL1):c.1133_1136dup (p.Cys380fs)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
3602619	NM_014271.4(IL1RAPL1):c.1118_1173dup (p.His392delinsValTrpTer)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
4057221	NM_014271.4(IL1RAPL1):c.230_243del (p.Tyr77fs)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
4533299	NM_014271.4(IL1RAPL1):c.1670dup (p.Tyr557Ter)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
4819660	NM_014271.4(IL1RAPL1):c.849G>C (p.Trp283Cys)	IL1RAPL1	Likely pathogenic	criteria provided, single submitter
1934211	NM_014271.4(IL1RAPL1):c.84C>T (p.Ala28=)	IL1RAPL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2432844	NM_014271.4(IL1RAPL1):c.82G>A (p.Ala28Thr)	IL1RAPL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
803783	NM_014271.4(IL1RAPL1):c.1910C>G (p.Thr637Ser)	IL1RAPL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
913474	NM_014271.4(IL1RAPL1):c.408T>C (p.Gly136=)	IL1RAPL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
913855	NM_014271.4(IL1RAPL1):c.1602G>A (p.Leu534=)	IL1RAPL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184394	NC_000023.11:g.29892903_29905635del	IL1RAPL1	Uncertain significance	criteria provided, single submitter
1333973	NM_014271.4(IL1RAPL1):c.1882T>C (p.Tyr628His)	IL1RAPL1	Uncertain significance	criteria provided, single submitter
1341849	NM_014271.4(IL1RAPL1):c.448T>G (p.Tyr150Asp)	IL1RAPL1	Uncertain significance	criteria provided, single submitter
1696453	NM_014271.4(IL1RAPL1):c.363-41213G>A	IL1RAPL1	Uncertain significance	criteria provided, single submitter
2432843	NM_014271.4(IL1RAPL1):c.1195G>A (p.Asp399Asn)	IL1RAPL1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
IL1RAPL1	Definitive	X-linked	intellectual disability, X-linked 21	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL1RAPL1	Orphanet:777	X-linked non-syndromic intellectual disability

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
IL1RAPL1	HGNC:5996	ENSG00000169306	Q9NZN1	Interleukin-1 receptor accessory protein-like 1	gencc,clinvar
ZNF611	HGNC:28766	ENSG00000213020	Q8N823	Zinc finger protein 611	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL1RAPL1	Interleukin-1 receptor accessory protein-like 1	May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel.
ZNF611	Zinc finger protein 611	May be involved in transcriptional regulation.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Antibody/Immunoglobulin	1	14.6×	0.135
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL1RAPL1	Antibody/Immunoglobulin	yes		TIR_dom, Ig_sub2, Ig_sub
ZNF611	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf

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
buccal mucosa cell	2
corpus callosum	1
endothelial cell	1
blood vessel layer	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL1RAPL1	115	broad	marker	buccal mucosa cell, endothelial cell, corpus callosum
ZNF611	275	ubiquitous	yes	buccal mucosa cell, renal medulla, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL1RAPL1	1,182
ZNF611	633

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL1RAPL1	Q9NZN1	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZNF611	Q8N823	64.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Interleukin-38 signaling	1	1427.5×	0.006	IL1RAPL1
Receptor-type tyrosine-protein phosphatases	1	285.5×	0.016	IL1RAPL1
Interleukin-1 family signaling	1	135.9×	0.017	IL1RAPL1
Protein-protein interactions at synapses	1	132.8×	0.017	IL1RAPL1
Signaling by Interleukins	1	32.1×	0.056	IL1RAPL1
Neuronal System	1	22.1×	0.062	IL1RAPL1
Cytokine Signaling in Immune system	1	20.4×	0.062	IL1RAPL1
Generic Transcription Pathway	1	7.5×	0.144	ZNF611
Immune System	1	6.5×	0.148	IL1RAPL1

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
trans-synaptic signaling by trans-synaptic complex	1	2808.7×	0.005	IL1RAPL1
negative regulation of exocytosis	1	1203.7×	0.005	IL1RAPL1
presynaptic membrane assembly	1	842.6×	0.005	IL1RAPL1
positive regulation of dendritic spine morphogenesis	1	443.5×	0.007	IL1RAPL1
synaptic membrane adhesion	1	290.6×	0.007	IL1RAPL1
regulation of presynapse assembly	1	271.8×	0.007	IL1RAPL1
regulation of postsynapse organization	1	263.3×	0.007	IL1RAPL1
regulation of neuron projection development	1	216.1×	0.008	IL1RAPL1
positive regulation of synapse assembly	1	122.1×	0.012	IL1RAPL1
neuron differentiation	1	50.1×	0.026	IL1RAPL1
cell surface receptor signaling pathway	1	32.0×	0.037	IL1RAPL1
positive regulation of DNA-templated transcription	1	14.0×	0.076	ZNF611
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ZNF611

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL1RAPL1	0	0
ZNF611	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	IL1RAPL1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ZNF611

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)
IL1RAPL1	0	—
ZNF611	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.