GeneBe

IL1RAPL1

protein-coding

interleukin 1 receptor accessory protein like 1, the group of TIR domain containing|MicroRNA protein coding host genes|I-set domain containing|Interleukin receptors

Gene summary

The protein encoded by this gene is a member of the interleukin 1 receptor family and is similar to the interleukin 1 accessory proteins. This protein has an N-terminal signal peptide, three extracellular immunoglobulin Ig-like domains, a transmembrane domain, an intracellular Toll/IL-1R domain, and a long C-terminal tail which interacts with multiple signalling molecules. This gene is located at a region on chromosome X that is associated with a non-syndromic form of X-linked intellectual disability. Deletions and mutations in this gene were found in patients with intellectual disability. This gene is expressed at a high level in post-natal brain structures involved in the hippocampal memory system, which suggests a specialized role in the physiological processes underlying memory and learning abilities, and plays a role in synapse formation and stabilization. [provided by RefSeq, Jul 2017]

Previous symbols:
  • IL1RAPL
  • MRX34
  • MRX21
  • MRX10

MANE transcript

NM_014271.4

Inheritance

XL

ClinVar variants

P:30U:164B:97

Top phenotype

Intellectual developmental disorder, X-linked 21

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chrX:28,587,446-29,956,718

External References & Databases

Ensembl (ENSG00000169306)NCBI Gene (11141)OMIM (300206)HGNC:5996GenCCUniProt (Q9NZN1)AlphaFoldClinVar (IL1RAPL1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~1,369.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 21MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010256

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked 21STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010256

Submitter: PanelApp Australia

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*IL1RAPL1* encodes a member of the interleukin-1 receptor family enriched at the postsynaptic density of excitatory synapses, where it acts as a synaptic adhesion molecule. *IL1RAPL1* was first reported in relation to X-linked complex neurodevelopmental disorder in 1999 (Carrié et al., PMID: 10471494). The clinical features of affected males include non-syndromic intellectual disability (ranging from borderline to profound) and autism spectrum disorder. Some individuals may exhibit additional features, such as nonspecific dysmorphic features and other behavioral issues. Carrier females are typically unaffected but some may have learning disabilities or autism (PMIDs: 16470793, 18801879, 21271657). Nine variants (frameshift, nonsense, and single gene deletions) that have been reported in nine probands in seven publications (PMIDs: 10471494, 16470793, 18801879, 19012350, 21271657, 26350204, 30555518) are included in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a mouse model (PMID: 28576939). In summary, there is definitive evidence supporting the relationship between *IL1RAPL1* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 30, 2017. It was reevaluated on August 31, 2026 (SOP Version 12). Although additional cases were added, the classification did not change.

intellectual developmental disorder, X-linked 21DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010256

Submitter: G2P

intellectual developmental disorder, X-linked 21DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010256

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked 21STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010256

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 21XL

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 8230164; 10471494; 16470793; 18005360; 19012350; 18801879; 21484992Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IL1RAPL1 variants in ClinVar

10 Conditions Cataloged
not providedTotal: 250
Intellectual disability, X-linked 21Total: 53
Inborn genetic diseasesTotal: 47
not specifiedTotal: 31
IL1RAPL1-related disorderTotal: 10
Intellectual disabilityTotal: 2
See casesTotal: 2
History of neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014271.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
6
clinvar
61
clinvar
12
clinvar
 79
missense
2
clinvar
149
clinvar
21
clinvar
3
clinvar
 175
nonsense
5
clinvar
6
clinvar
1
clinvar
 12
start loss
0
frameshift
2
clinvar
11
clinvar
1
clinvar
 14
splice donor/acceptor (+/-2bp)
2
clinvar
2
clinvar
7
clinvar
 11
Total9211648215291

Highest pathogenic variant AF is 9.1210086e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_014271.4RefSeqNP_055086.110MANE Select
ENST00000378993.6EnsemblENSP00000368278.110MANE Select
ENST00001135211.1EnsemblENSP00000810954.110Standard
XM_017029240.2RefSeqXP_016884729.110Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
il1rapl1bDanio rerio

Structure: olfactory receptor cell

Quality: increased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Signaling by Interleukins
  • Cytokine Signaling in Immune system
  • Immune System
  • Neuronal System
  • Receptor-type tyrosine-protein phosphatases

Biological Process

  • heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules
  • signal transduction
  • regulation of neuron projection development
  • neuron differentiation
  • negative regulation of exocytosis

Molecular Function

  • signaling receptor binding
  • voltage-gated calcium channel activity
  • protein binding
  • interleukin-1 binding

Cellular Component

  • cytoplasm
  • plasma membrane
  • cell surface
  • integral component of membrane
  • axon

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000378993
Coding exons
10
Length
1369325
Individuals with no LoFs
125709
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125711
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.771402670.5240.00002024572
Missense (PolyPhen)36120.020.299952089
Synonymous-0.006579796.91.000.000007611300
Loss of Function4.36124.10.04150.00000182424

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000250.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel (PubMed:12783849). May activate the MAP kinase JNK (PubMed:15123616). Plays a role in neurite outgrowth (By similarity). During dendritic spine formation can bidirectionally induce pre- and post-synaptic differentiation of neurons by trans- synaptically binding to PTPRD (By similarity). {ECO:0000250|UniProtKB:P59823, ECO:0000250|UniProtKB:P59824, ECO:0000269|PubMed:12783849, ECO:0000269|PubMed:15123616}.;

Recessive Scores

pRec
0.227

Intolerance Scores

RVIS EVS
-0.6
RVIS percentile EVS
17.75

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.801

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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