PIDD1

Summary

PIDD1 (p53-induced death domain protein 1, HGNC:16491) is a protein-coding gene on chromosome 11p15.5, encoding PIDD1 alternative open reading frame protein (C0HMD6).

The protein encoded by this gene contains a leucine-rich repeat and a death domain. This protein has been shown to interact with other death domain proteins, such as Fas (TNFRSF6)-associated via death domain (FADD) and MAP-kinase activating death domain-containing protein (MADD), and thus may function as an adaptor protein in cell death-related signaling processes. The expression of the mouse counterpart of this gene has been found to be positively regulated by the tumor suppressor p53 and to induce cell apoptosis in response to DNA damage, which suggests a role for this gene as an effector of p53-dependent apoptosis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55367 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 335 total — 10 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 30
• MANE Select transcript: NM_145886

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16491
Approved symbol	PIDD1
Name	p53-induced death domain protein 1
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	MGC16925, DKFZp434D229
Ensembl gene	ENSG00000177595
Ensembl biotype	protein_coding
OMIM	605247
Entrez	55367

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 protein_coding, 2 retained_intron

ENST00000347755, ENST00000411829, ENST00000524486, ENST00000525028, ENST00000527357, ENST00000527812, ENST00000528122, ENST00000530911, ENST00000531286, ENST00000534525, ENST00000534649

RefSeq mRNA: 2 — MANE Select: NM_145886 NM_145886, NM_145887

CCDS: CCDS44508, CCDS7716

Canonical transcript exons

ENST00000347755 — 16 exons

Exon	Start	End
ENSE00001528767	805179	805231
ENSE00001597904	803174	803587
ENSE00001836053	799184	799565
ENSE00003474887	800543	800666
ENSE00003478113	801445	801624
ENSE00003492957	800131	800244
ENSE00003515513	800762	800912
ENSE00003579847	799815	800014
ENSE00003598788	800333	800451
ENSE00003617749	801965	802090
ENSE00003660966	802195	802396
ENSE00003674212	801218	801365
ENSE00003685419	800985	801120
ENSE00003688414	802543	802597
ENSE00003689152	802682	802891
ENSE00003916597	804094	804463

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 91.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.6118 / max 135.7269, expressed in 1769 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117832	4.2645	1580
117830	3.3222	1225
117831	2.7931	1247
117829	2.2321	968

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	91.82	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.76	gold quality
right uterine tube	UBERON:0001302	90.19	gold quality
cervix squamous epithelium	UBERON:0006922	90.03	silver quality
cerebellar hemisphere	UBERON:0002245	89.95	gold quality
cerebellar cortex	UBERON:0002129	89.73	gold quality
granulocyte	CL:0000094	89.40	gold quality
mucosa of transverse colon	UBERON:0004991	89.05	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.52	gold quality
right lobe of thyroid gland	UBERON:0001119	88.34	gold quality
cerebellum	UBERON:0002037	88.21	gold quality
adenohypophysis	UBERON:0002196	88.20	gold quality
left lobe of thyroid gland	UBERON:0001120	88.06	gold quality
pituitary gland	UBERON:0000007	88.00	gold quality
skin of leg	UBERON:0001511	87.98	gold quality
right frontal lobe	UBERON:0002810	87.96	gold quality
gastrocnemius	UBERON:0001388	87.68	gold quality
body of stomach	UBERON:0001161	87.58	gold quality
right testis	UBERON:0004534	87.58	gold quality
tongue squamous epithelium	UBERON:0006919	87.20	silver quality
spinal cord	UBERON:0002240	86.95	gold quality
metanephros cortex	UBERON:0010533	86.93	gold quality
left testis	UBERON:0004533	86.89	gold quality
skin of abdomen	UBERON:0001416	86.84	gold quality
thyroid gland	UBERON:0002046	86.84	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.81	gold quality
lower esophagus mucosa	UBERON:0035834	86.67	gold quality
transverse colon	UBERON:0001157	86.64	gold quality
right lobe of liver	UBERON:0001114	86.58	gold quality
left ovary	UBERON:0002119	86.49	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	18.78
E-ANND-3	no	2.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

7 targeting PIDD1, 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-4306	99.72	70.50	3630
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-1178-3P	98.57	67.09	890
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683

Literature-anchored findings (GeneRIF, showing 25)

• activation of caspase-2 occurs in a complex that contains PIDD, whose expression is induced by p53, and RAIDD; increased PIDD expression resulted in spontaneous activation of caspase-2 and sensitization to apoptosis by genotoxic stimuli (PMID:15073321)
• PIDD plays a critical role in DNA-damage-induced NF-kappaB activation, controlling the balance between life and death upon DNA damage. (PMID:16360037)
• The functional consequences of the identified PIDD/nucleolin interaction remain to be elucidated, but may be related to a recently discovered new role for PIDD in the activation of NF-kappaB upon genotoxic stress. (PMID:16982033)
• PIDD autoproteolysis marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway (PMID:17159900)
• 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)
• No correlation between Pidd expression and the p53 mutation status of oral squamous cell carcinoma, suggesting that Pidd expression may be regulated by p53-independent mechanisms. (PMID:17437012)
• PIDD isoforms are capable of activating nuclear factor-kappaB in response to genotoxic stress, but only isoform 1 interacts with RIP-associated ICH-1/CED-3 homologous protein with a death domain and activates caspase-2. (PMID:17637755)
• p53-mediated apoptosis occurs by a PIDD- and caspase 2-dependent mechanism, and p53’s full transcriptional regulatory functions may be required only for events that are downstream of cytochrome c release (PMID:18238895)
• Total caspase-2 is 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)
• Hsp90 has a major role in controlling PIDD functional activity. (PMID:20966961)
• a new splicing variant of PIDD named PIDD4 is reported. (PMID:21371439)
• PIDD performs key functions upon UV irradiation, including TLS, NHEJ, NF-kappaB activation and cell death. (PMID:21415862)
• The ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury. (PMID:22854598)
• By sequestering PIDD at the kinetochore, BubR1 acts to delay PIDDosome formation until the next cycle, defining a new mechanism by which cells evade apoptosis during mitosis. (PMID:25936804)
• PIDD expression was lower in HCC tissues and HCC cell lines, compared with the adjacent non-tumorous tissues and LO2 normal hepatocytes. PIDD could serve as an independent prognostic factor to predict the survival of HCC patients. PIDD facilitated cell cycle progression and accelerated cell proliferation in HepG2 cells, while overexpression of PIDD resulted in cell cycle arrest at G1 phase in Hep3B cells. (PMID:26846109)
• NPM1-dependent nucleolar PIDDosome is a key initiator of the caspase-2 activation cascade. (PMID:28432080)
• 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)
• PIDD interaction with KEAP1 as a new mutation-independent mechanism to promote NRF2 stabilization and chemoresistance in NSCLC. (PMID:31455821)
• Attention-deficit/hyperactivity disorder risk alleles correlated with increased expression (and decreased methylation) of ARTN and PIDD1 and with a decreased expression (and increased methylation) of C2orf82. (PMID:31582733)
• ATR signalling mediates the prosurvival function of phospho-NPM against PIDDosome mediated cell death. (PMID:32194167)
• Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability. (PMID:33414379)
• Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features. (PMID:34163010)
• Molecular basis of neurodevelopmental disorders caused by pathogenic variants of PIDD. (PMID:36689811)
• Extra centrosomes induce PIDD1-mediated inflammation and immunosurveillance. (PMID:37530438)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pidd1	ENSMUSG00000025507
rattus_norvegicus	Pidd1	ENSRNOG00000049179

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), PHLPP1 (ENSG00000081913), SHOC2 (ENSG00000108061), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC8A (ENSG00000136802), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRK1 (ENSG00000154237), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8C (ENSG00000171488), LRRC8D (ENSG00000171492), SCRIB (ENSG00000180900), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954), LRRD1 (ENSG00000240720)

Protein

Protein identifiers

PIDD1 alternative open reading frame protein — C0HMD6 (reviewed: C0HMD6, Q9HB75)

Alternative names: altPIDD1

All UniProt accessions (3): E9PPT6, Q9HB75, H0YE55

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with calpain-2 catalytic subunit CAPN2.

Subcellular location. Cytoplasm. Cytoskeleton.

Post-translational modifications. Cleaved in vitro following UV irradiation to induce caspase-mediated apoptosis and this cleavage is inhibited by a broad-spectrum caspase inhibitor.

RefSeq proteins (2): NP_665893, NP_665894 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000906	ZU5_dom	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR019502	Peptidase_S68_pidd	Family
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family

Pfam: PF00531, PF00791, PF10461, PF13855

UniProt features (84 total): mutagenesis site 21, splice variant 10, region of interest 7, repeat 7, sequence variant 6, sequence conflict 6, helix 6, chain 5, active site 4, domain 3, modified residue 3, site 2, turn 2, compositionally biased region 1, initiator methionine 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2OF5	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-C0HMD6-F1	50.02	0.00
AF-Q9HB75-F1	78.60	0.19

Functional residue map

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

C0HMD6 (canonical)

Mutagenesis-validated functional residues (1):

Position	Phenotype
11	abolishes cleavage after uv irradiation.

Q9HB75

Catalytic / active sites (6): 444; 446; 586; 588; 445–446 (cleavage; by autolysis); 587–588 (cleavage; by autolysis)

Post-translational modifications (3): 2, 299, 305

Mutagenesis-validated functional residues (20):

Position	Phenotype
444	loss of the proteolytic cleavage producing pidd-c.
445	loss of the proteolytic cleavage producing pidd-c.
446	loss of the proteolytic cleavage producing pidd-c. unable to translocate to the nucleus upon dna damage. no effect on th
446	no effect on the proteolytic cleavage producing pidd-c.
582	loss of the proteolytic cleavage producing pidd-cc.
587	loss of the proteolytic cleavage producing pidd-cc.
588	loss of the proteolytic cleavage producing pidd-cc. loss of interaction with cradd and of the ability to activate casp2.
588	no effect on the proteolytic cleavage producing pidd-cc.
801	no effect on complex assembly with cradd.
814	loss of complex assembly with cradd. loss of piddosome assembly. loss of casp2 activation.
815	partial loss of complex assembly with cradd.
815	loss of complex assembly with cradd.
825	partial loss of complex assembly with cradd.
825	partial loss of complex assembly with cradd. decreased piddosome assembly. decreased casp2 activation.
826	partial loss of complex assembly with cradd.
828	loss of complex assembly with cradd.
830	no effect on complex assembly with cradd.
837	loss of complex assembly with cradd. loss of piddosome assembly. loss of casp2 activation.
862	loss of complex assembly with cradd. loss of piddosome assembly. loss of casp2 activation.
863	partial loss of complex assembly with cradd.

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: 195 (showing top): GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_PROTEIN_MATURATION, GOBP_APOPTOTIC_SIGNALING_PATHWAY, DOANE_RESPONSE_TO_ANDROGEN_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_DNA_DAMAGE_RESPONSE, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, LIAO_METASTASIS, GOBP_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, PID_P53_DOWNSTREAM_PATHWAY, GOBP_SIGNAL_TRANSDUCTION_IN_RESPONSE_TO_DNA_DAMAGE, SCHAVOLT_TARGETS_OF_TP53_AND_TP63, GOMF_SIGNALING_RECEPTOR_BINDING, MARTORIATI_MDM4_TARGETS_FETAL_LIVER_UP

GO Biological Process (12): apoptotic process (GO:0006915), DNA damage response (GO:0006974), signal transduction (GO:0007165), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), protein autoprocessing (GO:0016540), DNA damage response, signal transduction by p53 class mediator (GO:0030330), intracellular signal transduction (GO:0035556), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), regulation of canonical NF-kappaB signal transduction (GO:0043122), apoptotic signaling pathway (GO:0097190), extrinsic apoptotic signaling pathway (GO:0097191)

GO Molecular Function (4): endopeptidase activity (GO:0004175), death receptor binding (GO:0005123), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): cytoplasm (GO:0005737), cytoskeleton (GO:0005856), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), Golgi apparatus (GO:0005794), 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
cellular anatomical structure	3
apoptotic signaling pathway	2
intracellular anatomical structure	2
signal transduction	2
regulation of apoptotic process	2
intracellular membraneless organelle	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
cytoplasm	2
programmed cell death	1
execution phase of apoptosis	1
cellular response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
extrinsic apoptotic signaling pathway	1
protein processing	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
positive regulation of programmed cell death	1
negative regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of intracellular signal transduction	1
cell surface receptor signaling pathway	1
peptidase activity	1
tumor necrosis factor receptor superfamily binding	1
binding	1
catalytic activity	1
endomembrane system	1
peptidase complex	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

4 interactions, top by confidence:

A	B	Type	Score
PIDD1	CAPN2	psi-mi:“MI:0915”(physical association)	0.580
PIDD1	IPO5	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A1W2PPE3, A0A3B3IS91, A0A6I8MX38, A0A6I8PU40, A8MTW9, B1AH88, B3EWF7, C0HLS1, C0HMD6, H3BQW9, I3L0S3, I3L1E1, O70738, O75638, P03289, P0C880, P0DI83, P11300, P13985, P16807, P29164, P33485, P59091, P80612, Q01480, Q01900, Q3SYB3, Q5JLA7, Q5SY85, Q5T4H9, Q63003, Q6EEV4, Q6VB84, Q86SI9, Q8N1I8, Q8N1X5, Q8N319, Q8N6K4, Q8N6U2, Q8N726

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	4
Uncertain significance	223
Likely benign	52
Benign	13

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1686875	NM_145886.4(PIDD1):c.2275-1G>A	Pathogenic
1686876	NM_145886.4(PIDD1):c.2443C>T (p.Arg815Trp)	Pathogenic
1686877	NM_145886.4(PIDD1):c.2584C>T (p.Arg862Trp)	Pathogenic
1686878	NM_145886.4(PIDD1):c.2116_2120del (p.Val706fs)	Pathogenic
1686879	NM_145886.4(PIDD1):c.1804_1805del (p.Gly602fs)	Pathogenic
2167925	NM_145886.4(PIDD1):c.1635_1636del (p.Leu547fs)	Pathogenic
3366637	NM_145886.4(PIDD1):c.1819del (p.Ala607fs)	Pathogenic
3888664	NM_145886.4(PIDD1):c.989dup (p.Gln331fs)	Pathogenic
4056722	NM_145886.4(PIDD1):c.1917+1G>T	Pathogenic
929836	NM_145886.4(PIDD1):c.2587C>T (p.Gln863Ter)	Pathogenic
3254685	NM_145886.4(PIDD1):c.296-1G>A	Likely pathogenic
3370294	NM_145886.4(PIDD1):c.1302+1G>A	Likely pathogenic
3383979	NM_145886.4(PIDD1):c.1720del (p.Glu574fs)	Likely pathogenic
4056723	NM_145886.4(PIDD1):c.2214_2241del (p.Ala739fs)	Likely pathogenic

SpliceAI

2708 predictions. Top by Δscore:

Variant	Effect	Δscore
11:799809:CCTCA:C	donor_loss	1.0000
11:799810:CTCA:C	donor_loss	1.0000
11:799811:TCACC:T	donor_loss	1.0000
11:799812:CA:C	donor_loss	1.0000
11:799813:A:AC	donor_gain	1.0000
11:799814:C:CC	donor_gain	1.0000
11:800010:AGTCT:A	acceptor_gain	1.0000
11:800011:GTCT:G	acceptor_gain	1.0000
11:800012:TCTC:T	acceptor_loss	1.0000
11:800013:CT:C	acceptor_gain	1.0000
11:800014:TCTGT:T	acceptor_loss	1.0000
11:800015:C:CC	acceptor_gain	1.0000
11:800018:T:C	acceptor_gain	1.0000
11:800018:T:TC	acceptor_gain	1.0000
11:800118:C:CA	donor_gain	1.0000
11:800123:AGTC:A	donor_gain	1.0000
11:800136:G:C	donor_gain	1.0000
11:800178:T:TA	donor_gain	1.0000
11:800322:C:A	donor_gain	1.0000
11:800343:ACAG:A	donor_gain	1.0000
11:800344:CAGC:C	donor_gain	1.0000
11:800345:AG:A	donor_gain	1.0000
11:800346:G:GA	donor_gain	1.0000
11:800452:C:CC	acceptor_gain	1.0000
11:800537:CCCTA:C	donor_loss	1.0000
11:800538:CCTA:C	donor_loss	1.0000
11:800539:CTA:C	donor_loss	1.0000
11:800540:TAC:T	donor_loss	1.0000
11:800541:A:AC	donor_gain	1.0000
11:800541:A:T	donor_loss	1.0000

AlphaMissense

5725 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:802337:A:G	F345S	0.991
11:800581:A:G	F668S	0.989
11:800820:G:T	A620D	0.989
11:800411:G:C	F694L	0.988
11:800411:G:T	F694L	0.988
11:800413:A:G	F694L	0.988
11:800580:G:C	F668L	0.988
11:800580:G:T	F668L	0.988
11:800582:A:G	F668L	0.988
11:799882:A:G	W803R	0.987
11:799882:A:T	W803R	0.987
11:799880:C:A	W803C	0.985
11:799880:C:G	W803C	0.985
11:800387:C:A	K702N	0.985
11:800387:C:G	K702N	0.985
11:802783:T:A	N273I	0.984
11:800568:G:C	F672L	0.983
11:800568:G:T	F672L	0.983
11:800570:A:G	F672L	0.983
11:800779:A:G	C634R	0.983
11:802237:G:C	S378R	0.982
11:802237:G:T	S378R	0.982
11:802239:T:G	S378R	0.982
11:802851:G:C	N250K	0.982
11:802851:G:T	N250K	0.982
11:800236:G:C	F723L	0.981
11:800236:G:T	F723L	0.981
11:800238:A:G	F723L	0.981
11:800412:A:G	F694S	0.981
11:802782:G:C	N273K	0.981

dbSNP variants (sampled 300 via entrez): RS1000118985 (11:811147 A>G), RS1000200751 (11:804906 G>A), RS1000267176 (11:809693 G>A,C), RS1000272107 (11:811007 C>A,G), RS1000334289 (11:804929 T>C), RS1000340319 (11:809521 T>G), RS1000575527 (11:805077 A>C), RS1000609014 (11:805472 G>A), RS1001051325 (11:810435 A>C), RS1001230983 (11:801430 C>T), RS1001348826 (11:805712 A>AAGACCC), RS1001477704 (11:801810 G>A,C), RS1001497843 (11:810207 C>T), RS1001550169 (11:810009 TCTCCGC>T), RS1001586172 (11:808997 C>G,T)

Disease associations

OMIM: gene MIM:605247 | disease phenotypes: MIM:619827, MIM:609304

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly	Definitive	AR

Mondo (3): intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly (MONDO:0030785), developmental and epileptic encephalopathy, 3 (MONDO:0012245), intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000565	Esotropia
HP:0000709	Psychosis
HP:0000718	Aggressive behavior
HP:0000719	Inappropriate behavior
HP:0000752	Hyperactivity
HP:0000787	Nephrolithiasis
HP:0000953	Hyperpigmentation of the skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001302	Pachygyria
HP:0001339	Lissencephaly
HP:0002067	Bradykinesia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002197	Generalized-onset seizure
HP:0002354	Memory impairment
HP:0002360	Sleep disturbance
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0007164	Slowed slurred speech
HP:0011198	EEG with generalized epileptiform discharges
HP:0011463	Childhood onset
HP:0012169	Self-biting
HP:0012170	Nail-biting
HP:0012471	Thick vermilion border
HP:0020045	Esodeviation
HP:0100716	Self-injurious behavior

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004988_677	Breast cancer	1.000000e-12
GCST90013442_17	Keratoconus	1.000000e-26

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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects cotreatment, increases expression, decreases methylation	5
Cisplatin	affects expression, affects cotreatment, increases expression	4
sodium arsenite	increases abundance, increases expression, decreases expression	3
bisphenol A	increases methylation, affects cotreatment, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Copper	affects binding, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	affects expression, increases methylation	2
Aflatoxin B1	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	increases expression	1
moringin	affects cotreatment, decreases expression	1
beauvericin	decreases expression	1
chloroacetaldehyde	decreases expression	1
naringenin	affects cotreatment, increases expression	1
benzo(b)fluoranthene	affects cotreatment, increases expression	1
quercitrin	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
periodate-oxidized adenosine	affects expression	1
benz(a)anthracene	affects cotreatment, increases expression	1
chrysene	affects cotreatment, increases expression	1
leptomycin B	increases expression	1
avobenzone	increases expression	1
adefovir dipivoxil	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1

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