CRADD

Summary

CRADD (CARD and death domain containing adaptor protein, HGNC:2340) is a protein-coding gene on chromosome 12q22, encoding Death domain-containing protein CRADD (P78560). Adapter protein that associates with PIDD1 and the caspase CASP2 to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis.

This gene encodes a protein containing a death domain (DD) motif. This protein recruits caspase 2/ICH1 to the cell death signal transduction complex, which includes tumor necrosis factor receptor 1 (TNFR1A) and RIPK1/RIP kinase, and acts in promoting apoptosis. A mutation in this gene was associated with cognitive disability. A related pseudogene is found on chromosome 3. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8738 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 40
• Clinical variants (ClinVar): 92 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 9
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003805

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2340
Approved symbol	CRADD
Name	CARD and death domain containing adaptor protein
Location	12q22
Locus type	gene with protein product
Status	Approved
Aliases	RAIDD
Ensembl gene	ENSG00000169372
Ensembl biotype	protein_coding
OMIM	603454
Entrez	8738

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 6 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000332896, ENST00000542893, ENST00000547383, ENST00000548330, ENST00000548483, ENST00000549615, ENST00000550030, ENST00000550766, ENST00000551065, ENST00000552033, ENST00000552983, ENST00000609189, ENST00000880420, ENST00000918988

RefSeq mRNA: 5 — MANE Select: NM_003805 NM_001320099, NM_001320100, NM_001320101, NM_001330126, NM_003805

CCDS: CCDS81719, CCDS81720, CCDS81722, CCDS9048

Canonical transcript exons

ENST00000332896 — 3 exons

Exon	Start	End
ENSE00001274256	93677375	93677472
ENSE00003526929	93678769	93679072
ENSE00003583423	93849970	93850756

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 91.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.2300 / max 50.0332, expressed in 1727 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127375	6.0396	1720
127376	0.1735	66
127388	0.0168	4

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.20	gold quality
heart left ventricle	UBERON:0002084	90.53	gold quality
cardiac ventricle	UBERON:0002082	90.21	gold quality
right lobe of liver	UBERON:0001114	90.15	gold quality
apex of heart	UBERON:0002098	89.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.81	gold quality
islet of Langerhans	UBERON:0000006	88.75	gold quality
right atrium auricular region	UBERON:0006631	88.70	gold quality
heart	UBERON:0000948	88.61	gold quality
right testis	UBERON:0004534	88.41	gold quality
left testis	UBERON:0004533	88.05	gold quality
left adrenal gland	UBERON:0001234	88.04	gold quality
right adrenal gland	UBERON:0001233	87.81	gold quality
left adrenal gland cortex	UBERON:0035825	87.75	gold quality
muscle of leg	UBERON:0001383	87.51	gold quality
cardiac atrium	UBERON:0002081	87.46	gold quality
gastrocnemius	UBERON:0001388	87.21	gold quality
liver	UBERON:0002107	87.21	gold quality
right adrenal gland cortex	UBERON:0035827	87.14	gold quality
cartilage tissue	UBERON:0002418	87.13	gold quality
adrenal tissue	UBERON:0018303	86.82	gold quality
adrenal gland	UBERON:0002369	86.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.40	gold quality
testis	UBERON:0000473	86.33	gold quality
adrenal cortex	UBERON:0001235	86.23	gold quality
triceps brachii	UBERON:0001509	86.22	gold quality
endometrium epithelium	UBERON:0004811	86.08	gold quality
paraflocculus	UBERON:0005351	85.81	gold quality
muscle organ	UBERON:0001630	85.71	gold quality
frontal pole	UBERON:0002795	85.46	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting CRADD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-3922-3P	99.25	64.96	1136

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 13)

• As a first step towards elucidating the molecular mechanisms of caspase-2 activation, data report the crystal structure of the RAIDD death domain at 2.0 A resolution. (PMID:16434054)
• PIDD death domain (DD) and RAIDD DD assemble into an oligomeric complex. Within the PIDDosome, the interaction between PIDD and RAIDD is mediated by a homotypic interaction between their death domains. (PMID:17329820)
• impaired expression of RAIDD in drug induced apoptosis may play a role in the multidrug resistance of osteosarcoma cells (PMID:19125251)
• Crystals are trigonal and belong to space group P3(1)21 (or its enantiomorph P3(2)21) with unit-cell parameters a = 56.3, b = 56.3, c = 64.9 A and gamma = 120 degrees . (PMID:19582216)
• The expressions of PIDD and RAIDD are upregulated during tumour progression in renal cell carcinomas. (PMID:20208132)
• point mutations on RAIDD (R147E) and on PIDD (Y814A) exert a dominant negative effect on the formation of the PIDDosome, and that this effect cannot be applied after the PIDDosome has been formed (PMID:20406701)
• Study identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. (PMID:22279524)
• define a novel function for CRADD in endothelial cells as an inducible suppressor of BCL10, a key mediator of responses to proinflammatory agonists (PMID:24958727)
• The adaptor molecule RAIDD coordinates IKKepsilon and IRF7 interaction to ensure efficient expression of type I interferon. (PMID:27606466)
• The megalencephaly, lissencephaly variant, and intellectual disability associated with loss of CRADD/caspase-2-mediated apoptosis imply a role for CRADD/caspase-2 signaling in development of the human cerebral cortex. (PMID:27773430)
• Whole exome sequencing (WES) of an affected fetus, and subsequent Sanger sequencing of the second fetus, revealed a homozygous frameshift variant in CRADD, which encodes an adaptor protein that interacts with PIDD and caspase-2 to initiate apoptosis (PMID:28686357)
• Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in ASP2 and RIPK1 domain containing adaptor with death domain protein CRADD (CRADD). (PMID:30914828)
• CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies. (PMID:33647455)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cradd	ENSDARG00000028192
mus_musculus	Cradd	ENSMUSG00000045867
rattus_norvegicus	Cradd	ENSRNOG00000008507

Protein

Protein identifiers

Death domain-containing protein CRADD — P78560 (reviewed: P78560)

Alternative names: Caspase and RIP adapter with death domain, RIP-associated protein with a death domain

All UniProt accessions (5): F5H7C2, F8VV49, F8VVY5, P78560, Q53XL1

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that associates with PIDD1 and the caspase CASP2 to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis. Also recruits CASP2 to the TNFR-1 signaling complex through its interaction with RIPK1 and TRADD and may play a role in the tumor necrosis factor-mediated signaling pathway.

Subunit / interactions. Forms a complex named the PIDDosome with PIDD1 and CASP2. Interacts (via Death domain) with RIPK1 (via Death domain); the interaction is direct. Interacts with TRADD. Interacts with TNFRSF1A.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Constitutively expressed in most tissues, with particularly high expression in adult heart, testis, liver, skeletal muscle, fetal liver and kidney.

Disease relevance. Intellectual developmental disorder, autosomal recessive 34, with variant lissencephaly (MRT34) [MIM:614499] A disorder characterized by mild to moderate intellectual disability, megalencephaly or enlarged head circumference, and a mild variant of lissencephaly with anterior-predominant pachygyria with shallow and unusually wide sulci and mildly thickened cortex. Some patients may have seizures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Death domain mediates the interaction with PIDD1 and the formation of a complex composed of 5 PIDD1 and 7 CRADD proteins which in turn probably recruit 7 CASP2 to form the PIDDosome. The Death domain mediates a direct interaction with the Death domain of RIPK1. The CARD domain mediates a direct interaction with CASP2.

Isoforms (2)

UniProt ID	Names	Canonical?
P78560-1	1	yes
P78560-2	2

RefSeq proteins (5): NP_001307028, NP_001307029, NP_001307030, NP_001317055, NP_003796* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR001315	CARD	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR037926	CRADD_Death	Domain
IPR037939	CRADD	Family
IPR042148	CARD_RAIDD	Domain

Pfam: PF00531, PF00619

UniProt features (38 total): mutagenesis site 17, helix 14, domain 2, chain 1, strand 1, turn 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2O71	X-RAY DIFFRACTION	2
2OF5	X-RAY DIFFRACTION	3.2
3CRD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78560-F1	79.97	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (17):

Position	Phenotype
142	partial loss of interaction with pidd1.
146	loss of interaction with pidd1. decreased piddosome assembly. decreased casp2 activation.
147	loss of interaction with pidd1. decreased piddosome assembly. decreased casp2 activation.
147	loss of interaction with pidd1. loss of piddosome assembly. loss of casp2 activation.
149	loss of interaction with pidd1.
154	partial loss of interaction with pidd1.
156	loss of interaction with pidd1. loss of piddosome assembly. loss of casp2 activation.
169	partial loss of interaction with pidd1. decreased piddosome assembly. decreased casp2 activation.
169	loss of interaction with pidd1.
170	partial loss of interaction with pidd1.
188	no effect on interaction with pidd1.
189	no effect on interaction with pidd1.
27	loss of interaction with casp2.
65	loss of interaction with casp2.
121	loss of interaction with pidd1.
125	loss of interaction with pidd1.
136	partial loss of interaction with pidd1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6803207	TP53 Regulates Transcription of Caspase Activators and Caspases

MSigDB gene sets: 217 (showing top): GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, GOBP_APOPTOTIC_SIGNALING_PATHWAY, BLALOCK_ALZHEIMERS_DISEASE_UP, BROWNE_HCMV_INFECTION_14HR_DN, HSIAO_LIVER_SPECIFIC_GENES, JAZAG_TGFB1_SIGNALING_VIA_SMAD4_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, GOBP_DNA_DAMAGE_RESPONSE, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, BIOCARTA_HIVNEF_PATHWAY, GOBP_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR

GO Biological Process (10): DNA damage response (GO:0006974), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), DNA damage response, signal transduction by p53 class mediator (GO:0030330), positive regulation of apoptotic process (GO:0043065), cellular response to mechanical stimulus (GO:0071260), apoptotic signaling pathway (GO:0097190), positive regulation of apoptotic signaling pathway (GO:2001235), apoptotic process (GO:0006915), signal transduction (GO:0007165), regulation of apoptotic process (GO:0042981)

GO Molecular Function (4): protease binding (GO:0002020), protein-macromolecule adaptor activity (GO:0030674), death domain binding (GO:0070513), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), endopeptidase complex (GO:1905369)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TP53 Regulates Transcription of Cell Death Genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic process	3
apoptotic signaling pathway	2
cellular anatomical structure	2
cellular response to stress	1
extrinsic apoptotic signaling pathway	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
signal transduction	1
positive regulation of signal transduction	1
positive regulation of apoptotic process	1
regulation of apoptotic signaling pathway	1
programmed cell death	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of programmed cell death	1
enzyme binding	1
protein binding	1
molecular adaptor activity	1
protein domain specific binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
peptidase complex	1

Protein interactions and networks

STRING

524 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRADD	CASP2	P42575	999
CRADD	PIDD1	Q9HB75	999
CRADD	TRADD	Q15628	980
CRADD	FADD	Q13158	967
CRADD	CYFIP2	Q96F07	934
CRADD	APAF1	O14727	745
CRADD	MINDY3	Q9H8M7	727
CRADD	RIPK2	O43353	689
CRADD	RIPK1	Q13546	628
CRADD	CASP1	P29466	623
CRADD	CFLAR	O15519	616
CRADD	NOD1	Q9Y239	605
CRADD	TNFRSF1A	P19438	591
CRADD	TP53	P04637	586
CRADD	DIABLO	Q9NR28	573

IntAct

72 interactions, top by confidence:

A	B	Type	Score
CASP2	CRADD	psi-mi:“MI:0915”(physical association)	0.970
CRADD	CASP2	psi-mi:“MI:0915”(physical association)	0.970
CASP2	CRADD	psi-mi:“MI:2364”(proximity)	0.970
CRADD	CASP2	psi-mi:“MI:2364”(proximity)	0.970
CASP2	CRADD	psi-mi:“MI:0914”(association)	0.970
CRADD	CASP2	psi-mi:“MI:0914”(association)	0.970
CRADD	PIDD1	psi-mi:“MI:0915”(physical association)	0.800
PIDD1	CRADD	psi-mi:“MI:0915”(physical association)	0.800

BioGRID (43): CRADD (Two-hybrid), KCTD9 (Two-hybrid), APPL2 (Two-hybrid), TRIM54 (Two-hybrid), BBS5 (Two-hybrid), CRADD (Two-hybrid), CRADD (Affinity Capture-RNA), CASP2 (Two-hybrid), WIF1 (Two-hybrid), CRADD (Affinity Capture-Western), CRADD (Affinity Capture-Western), CRADD (Affinity Capture-MS), CRADD (Affinity Capture-Western), C14orf1 (Two-hybrid), EEF1A1 (Two-hybrid)

ESM2 similar proteins: A2VE14, B1H1Z8, B4ZIX8, D3ZVR7, O88843, O89050, P35790, P78560, Q05B84, Q0VCJ8, Q15831, Q3MHQ0, Q4R539, Q5EA19, Q5H8A4, Q5NVN7, Q5R4Q7, Q5R6I4, Q5RB35, Q5RFN0, Q5RKN4, Q5ZJB7, Q5ZMH6, Q6AXQ0, Q6IA17, Q86WI3, Q86XW9, Q8BGR6, Q8IUI8, Q8N653, Q92565, Q96MZ0, Q96NJ5, Q96NT3, Q99PV3, Q9BTV5, Q9CQ33, Q9D2X5, Q9EPL4, Q9H1A3

Diamond homologs: O88843, P42575, P78560, Q5R6I4, P55215

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CRADD	“form complex”	“Caspase-2 PIDDosome”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

92 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	36
Likely benign	30
Benign	9

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1458241	NM_003805.5(CRADD):c.52_59del (p.Ala18fs)	Pathogenic
2424767	NC_000012.11:g.(?94243726)(94244047_?)del	Pathogenic
372190	NM_003805.5(CRADD):c.508C>T (p.Arg170Cys)	Pathogenic
372191	NM_003805.5(CRADD):c.509G>A (p.Arg170His)	Pathogenic
870252	NM_003805.5(CRADD):c.2T>G (p.Met1Arg)	Pathogenic
981900	NM_003805.5(CRADD):c.2T>C (p.Met1Thr)	Pathogenic
3575538	NM_003805.5(CRADD):c.50del (p.Gly17fs)	Likely pathogenic
915343	NM_003805.5(CRADD):c.298+59160del	Likely pathogenic

SpliceAI

2270 predictions. Top by Δscore:

Variant	Effect	Δscore
12:93849872:G:GT	donor_gain	1.0000
12:93677470:GAC:G	donor_gain	0.9900
12:93677473:G:GG	donor_gain	0.9900
12:93678764:TCCA:T	acceptor_loss	0.9900
12:93678766:CAGG:C	acceptor_loss	0.9900
12:93678768:GGGA:G	acceptor_gain	0.9900
12:93678871:G:GT	donor_gain	0.9900
12:93679070:CAG:C	donor_loss	0.9900
12:93679071:AG:A	donor_loss	0.9900
12:93679072:GG:G	donor_loss	0.9900
12:93679073:G:GC	donor_loss	0.9900
12:93679074:T:G	donor_loss	0.9900
12:93758085:A:G	acceptor_gain	0.9900
12:93815482:G:GG	donor_gain	0.9900
12:93849965:CTCA:C	acceptor_loss	0.9900
12:93849966:TCA:T	acceptor_loss	0.9900
12:93849968:A:C	acceptor_loss	0.9900
12:93849969:G:GC	acceptor_loss	0.9900
12:93677468:CAGAC:C	donor_gain	0.9800
12:93677469:AGACG:A	donor_loss	0.9800
12:93677471:ACG:A	donor_loss	0.9800
12:93677472:CG:C	donor_loss	0.9800
12:93677473:G:C	donor_loss	0.9800
12:93677474:T:A	donor_loss	0.9800
12:93677484:G:GT	donor_gain	0.9800
12:93678767:AG:A	acceptor_gain	0.9800
12:93678768:GG:G	acceptor_gain	0.9800
12:93679045:G:T	donor_gain	0.9800
12:93746487:G:T	donor_gain	0.9800
12:93849968:A:AG	acceptor_gain	0.9800

AlphaMissense

1283 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:93678956:T:A	L61Q	0.997
12:93678800:T:A	L9H	0.996
12:93678956:T:C	L61P	0.996
12:93678989:T:C	F72S	0.996
12:93850170:T:A	W167R	0.996
12:93850170:T:C	W167R	0.996
12:93678881:T:C	L36S	0.995
12:93678956:T:G	L61R	0.995
12:93679009:T:C	F79L	0.995
12:93679011:T:A	F79L	0.995
12:93679011:T:G	F79L	0.995
12:93678944:T:C	L57P	0.994
12:93678947:T:C	L58P	0.994
12:93678979:T:C	F69L	0.994
12:93678981:T:A	F69L	0.994
12:93678981:T:G	F69L	0.994
12:93679001:T:C	L76P	0.994
12:93850062:T:A	W131R	0.994
12:93850062:T:C	W131R	0.994
12:93678800:T:C	L9P	0.993
12:93679031:T:C	L86P	0.993
12:93678863:T:C	L30P	0.992
12:93679015:T:A	W81R	0.991
12:93679015:T:C	W81R	0.991
12:93678947:T:A	L58Q	0.990
12:93850172:G:C	W167C	0.989
12:93850172:G:T	W167C	0.989
12:93679017:G:C	W81C	0.988
12:93679017:G:T	W81C	0.988
12:93850210:T:C	L180P	0.988

dbSNP variants (sampled 300 via entrez): RS1000003347 (12:93884139 G>C), RS1000004095 (12:93679632 G>A), RS1000018430 (12:93789028 C>G,T), RS1000044670 (12:93738508 C>A,G,T), RS1000071287 (12:93700216 T>C), RS1000094378 (12:93693435 G>C), RS1000104598 (12:93842721 T>C), RS1000105341 (12:93877784 C>G), RS1000109225 (12:93753723 G>T), RS1000111325 (12:93890484 T>G), RS1000117591 (12:93819596 G>C), RS1000119968 (12:93700620 CGG>C), RS1000133005 (12:93724930 G>A), RS1000163450 (12:93864123 T>C), RS1000165999 (12:93706971 A>T)

Disease associations

OMIM: gene MIM:603454 | disease phenotypes: MIM:614499, MIM:107970

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 34	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AR

Mondo (4): intellectual disability, autosomal recessive 34 (MONDO:0013785), familial isolated arrhythmogenic right ventricular dysplasia (MONDO:0016342), intellectual disability (MONDO:0001071), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (3): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Inherited isolated arrhythmogenic cardiomyopathy (Orphanet:217656), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001302	Pachygyria
HP:0001339	Lissencephaly
HP:0001355	Megalencephaly
HP:0002069	Bilateral tonic-clonic seizure
HP:0040194	Increased head circumference

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000175_22	Height	2.000000e-07
GCST001915_29	Alzheimer’s disease (cognitive decline)	5.000000e-08
GCST002647_51	Height	5.000000e-33
GCST004067_158	Hip circumference adjusted for BMI	2.000000e-08
GCST004067_21	Hip circumference adjusted for BMI	2.000000e-16
GCST004067_216	Hip circumference adjusted for BMI	1.000000e-11
GCST006288_153	Heel bone mineral density	4.000000e-07
GCST006288_19	Heel bone mineral density	2.000000e-10
GCST006483_10	Lung function (FVC)	4.000000e-08
GCST006979_1077	Heel bone mineral density	7.000000e-18
GCST007096_191	Pulse pressure	4.000000e-08
GCST007429_148	Lung function (FVC)	4.000000e-07
GCST008053_96	Height	2.000000e-09
GCST008163_548	Height	7.000000e-10
GCST008359_5	Response to cognitive-behavioural therapy in anxiety disorder	2.000000e-06
GCST008839_154	Height	1.000000e-52
GCST008839_544	Height	1.000000e-20
GCST008839_60	Height	6.000000e-09
GCST008839_65	Height	3.000000e-34
GCST009798_83	Asthma	6.000000e-11
GCST010396_19	Gut microbiota (bacterial taxa, hurdle binary method)	6.000000e-06
GCST012226_324	Waist circumference adjusted for body mass index	5.000000e-08
GCST012227_541	Hip circumference adjusted for BMI	3.000000e-11
GCST012227_542	Hip circumference adjusted for BMI	3.000000e-16
GCST012227_543	Hip circumference adjusted for BMI	5.000000e-14
GCST012227_544	Hip circumference adjusted for BMI	6.000000e-10
GCST012227_545	Hip circumference adjusted for BMI	5.000000e-11
GCST012227_546	Hip circumference adjusted for BMI	8.000000e-12
GCST90000025_984	Appendicular lean mass	3.000000e-64
GCST90002385_235	High light scatter reticulocyte count	1.000000e-12

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0009270	heel bone mineral density
EFO:0004312	vital capacity
EFO:0005763	pulse pressure measurement
EFO:0007820	cognitive behavioural therapy
EFO:0007874	gut microbiome measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	5
bisphenol A	affects cotreatment, affects methylation, decreases expression, decreases methylation, increases expression	3
Aflatoxin B1	decreases expression, decreases methylation	3
epigallocatechin gallate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
moringin	affects cotreatment, increases expression	1
naringenin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
usnic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
NSC 674495	affects response to substance	1
abrine	increases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Acetaminophen	decreases expression	1
Acetylcysteine	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
alpha-Chlorohydrin	decreases expression	1
Benzene	increases expression	1
Cannabidiol	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ozone	affects expression, increases abundance	1

Cellosaurus cell lines

5 cell lines: 5 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_VJ20	GM25977	Finite cell line	Female
CVCL_VJ21	GM25978	Finite cell line	Male
CVCL_VJ22	GM25979	Finite cell line	Male
CVCL_VJ23	GM25980	Finite cell line	Male
CVCL_VJ24	GM25981	Finite cell line	Female

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders