ADNP

Summary

ADNP (activity dependent neuroprotector homeobox, HGNC:15766) is a protein-coding gene on chromosome 20q13.13, encoding Activity-dependent neuroprotector homeobox protein (Q9H2P0). May be involved in transcriptional regulation. It is a selective cancer dependency (DepMap: 12.6% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

Vasoactive intestinal peptide is a neuroprotective factor that has a stimulatory effect on the growth of some tumor cells and an inhibitory effect on others. This gene encodes a protein that is upregulated by vasoactive intestinal peptide and may be involved in its stimulatory effect on certain tumor cells. The encoded protein contains one homeobox and nine zinc finger domains, suggesting that it functions as a transcription factor. This gene is also upregulated in normal proliferative tissues. Finally, the encoded protein may increase the viability of certain cell types through modulation of p53 activity. Alternatively spliced transcript variants encoding the same protein have been described.

Source: NCBI Gene 23394 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 915 total — 117 pathogenic, 49 likely-pathogenic
• Phenotypes (HPO): 168
• Cancer dependency (DepMap): dependent in 12.6% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001282531

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15766
Approved symbol	ADNP
Name	activity dependent neuroprotector homeobox
Location	20q13.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0784, ADNP1
Ensembl gene	ENSG00000101126
Ensembl biotype	protein_coding
OMIM	611386
Entrez	23394

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 16 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000349014, ENST00000371602, ENST00000396029, ENST00000396032, ENST00000621696, ENST00000642364, ENST00000644386, ENST00000645081, ENST00000673732, ENST00000908532, ENST00000908533, ENST00000933179, ENST00000933180, ENST00000933181, ENST00000933182, ENST00000971605, ENST00000971606

RefSeq mRNA: 5 — MANE Select: NM_001282531 NM_001282531, NM_001282532, NM_001347511, NM_015339, NM_181442

CCDS: CCDS13433

Canonical transcript exons

ENST00000621696 — 6 exons

Exon	Start	End
ENSE00000662817	50902017	50902109
ENSE00001280942	50928651	50928825
ENSE00001385896	50930826	50931437
ENSE00001455633	50903889	50904001
ENSE00002158531	50904766	50904849
ENSE00003724220	50888918	50894512

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.1033 / max 614.4122, expressed in 1824 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187903	42.9561	1820
187900	7.4419	1627
187897	2.8496	1333
187901	2.2777	1067
187902	1.6755	871
187893	0.9026	362
187895	0.5917	365
187899	0.4552	272
187894	0.3862	206
187898	0.3857	192

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.78	gold quality
cortical plate	UBERON:0005343	97.61	gold quality
ventricular zone	UBERON:0003053	97.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	97.06	gold quality
embryo	UBERON:0000922	96.94	gold quality
germinal epithelium of ovary	UBERON:0001304	96.06	gold quality
corpus epididymis	UBERON:0004359	95.85	gold quality
cauda epididymis	UBERON:0004360	95.14	gold quality
caput epididymis	UBERON:0004358	95.00	gold quality
palpebral conjunctiva	UBERON:0001812	94.99	gold quality
endometrium epithelium	UBERON:0004811	94.75	gold quality
skin of hip	UBERON:0001554	94.74	gold quality
adult organism	UBERON:0007023	94.74	gold quality
upper leg skin	UBERON:0004262	94.39	gold quality
pigmented layer of retina	UBERON:0001782	94.31	gold quality
epithelium of nasopharynx	UBERON:0001951	94.13	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.13	gold quality
amniotic fluid	UBERON:0000173	94.07	gold quality
mammary duct	UBERON:0001765	94.06	gold quality
endometrium	UBERON:0001295	94.04	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.92	gold quality
biceps brachii	UBERON:0001507	93.84	gold quality
sperm	CL:0000019	93.72	gold quality
epithelium of mammary gland	UBERON:0003244	93.68	gold quality
parotid gland	UBERON:0001831	93.46	gold quality
colonic epithelium	UBERON:0000397	93.36	gold quality
parietal pleura	UBERON:0002400	93.32	gold quality
testis	UBERON:0000473	93.29	gold quality
oral cavity	UBERON:0000167	93.24	gold quality
urinary bladder	UBERON:0001255	93.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-98556	no	1706.92
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
BECN1	Activation

miRNA regulators (miRDB)

123 targeting ADNP, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-30A-3P	99.87	69.74	2928

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 12.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 39)

• Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex. (PMID:17878164)
• ADNP is expressed in many immune system cells. ADNP mRNA is reduced in PBMCs in MS. The peptide NAP, which plays an important role in neuroprotection, has potential immunomodulatory properties. (PMID:19923857)
• In the prefrontal cortex of schizophrenia patients the correlation between ADNP and ADNP2 mRNA levels was apparently higher than in the hippocampus (r=0.854, p<0.001), but did not reach a significant difference (p=0.25). (PMID:20598862)
• Chromatin immunoprecipitation demonstrates the ability of ADNP to bind to its own promoter, consistent with its action as a repressor of both promoter-supported and endogenous ADNP expression. (PMID:21647709)
• Our results suggested that ADNP may play an important role in slowing the progression of clinical symptoms of AD. (PMID:22554909)
• This study showed ADNP that deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients. (PMID:24365867)
• Ten patients with autism spectrum disorders and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. (PMID:24531329)
• Mutations in the ADNP gene cause syndromic autism.Ample evidence exists that ADNP is of key importance for proper functioning of the nBAF complex. (PMID:25169753)
• ADNP expression was increased in male hippocampus samples compared to female samples. (PMID:25646590)
• This review covers the myriad of important ADNP-protein interactions and glimpse at their potential meaning in autism, schizophrenia and Alzheimer’s disease. [review] (PMID:25955282)
• These findings demonstrate that the down-regulation of protein ADNP is an early pathological alteration and may contribute to dopaminergic neurodegeneration in Parkinson’s disease (PMID:27003787)
• The study identified intratumoral heterogeneity (ITH) of the ADNP mutations in colorectal cancers, suggesting that ADNP mutations occurred during tumor progression rather than as an early event. The generation of ITH may influence on clinical outcome of the cancer patients. (PMID:27308845)
• SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset describing the genes associated with autism spectrum disorders. (PMID:27790361)
• Our findings indicate that ADNP is a tumor suppressor and promising prognostic marker, and that ketamine treatment with ADNP induction is a potential therapeutic approach that may add benefit to current treatment protocols for patients with colorectal cancer (PMID:27903678)
• The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars and only 10 of the children had teeth within the normal developmental time range. (PMID:28221363)
• From a clinical standpoint, a differential diagnosis of patients with blepharophimosis should include ADNP mutations in addition to blepharophimosis ptosis epicanthus inversus syndrome, especially when intellectual disability is present (PMID:28407407)
• The role of ADNP in autophagy, and in autism, schizophrenia and Alzheimer’s disease is described. (PMID:28940660)
• in patients with intellectual disability, autism spectrum disorder and features suggestive of Noonan syndrome should have DNA analysis for the ADNP gene if the Noonan syndrome panel failed to identify a specific mutation. (PMID:29424797)
• This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. It shows that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. (PMID:29724491)
• These results suggest a correlation between the position of the mutations across ADNP protein, its stability and subcellular localization. (PMID:29911927)
• Heterozygous mutations involving ADNP have been identified in multiple individuals with autism spectrum disorder providing strong evidence that ADNP is an autism risk gene. (PMID:30107084)
• Our observations provide a novel activity of the autism-linked ADNP in the skin that may serve to define the clinical phenotype of patients with ADNP syndrome and provide an attractive therapeutic option for skin alterations in these patients. (PMID:30679581)
• Study describes two distinct episignatures caused by mutations within ADNP. The “epi-ADNP-1” episignature included mostly hypomethylated CpGs, and the “epi-ADNP-2” episignature included predominantly hypermethylated ones. Both of them correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. (PMID:31029150)
• Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: mutated ADNP cytoskeletal impairments and repair as a case study. (PMID:31664177)
• We identified ADNP as being amplified and overexpressed in poor prognosis HGSOC in silico analyses and demonstrated that ADNP is a novel and essential oncogene in HGSOC which mediates proliferation through dysregulation of cell cycle checkpoints in vitro. (PMID:31767542)
• Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype. (PMID:32758449)
• Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting. (PMID:33086621)
• Introducing ADNP and SIRT1 as new partners regulating microtubules and histone methylation. (PMID:33967268)
• Novel ADNP Syndrome Mice Reveal Dramatic Sex-Specific Peripheral Gene Expression With Brain Synaptic and Tau Pathologies. (PMID:34865853)
• Distinct Impairments Characterizing Different ADNP Mutants Reveal Aberrant Cytoplasmic-Nuclear Crosstalk. (PMID:36230962)
• Activity-Dependent Neuroprotective Protein (ADNP): An Overview of Its Role in the Eye. (PMID:36362439)
• Modulatory activity of ADNP on the hypoxiainduced angiogenic process in glioblastoma. (PMID:36484392)
• A novel davunetide (NAPVSIPQQ to NAPVSIPQE) point mutation in activity-dependent neuroprotective protein (ADNP) causes a mild developmental syndrome. (PMID:36669790)
• Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism. (PMID:36945042)
• ADNP is associated with immune infiltration and radiosensitivity in hepatocellular carcinoma for predicting the prognosis. (PMID:37525242)
• [Helsmoortel-Van der Aa syndrome due to hotspot mutation of ADNP gene and a literature review]. (PMID:37906146)
• Clinical impact and in vitro characterization of ADNP variants in pediatric patients. (PMID:38254177)
• Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males. (PMID:38282129)
• Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions. (PMID:38622540)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adnpb	ENSDARG00000074293
mus_musculus	Adnp	ENSMUSG00000051149
rattus_norvegicus	Adnp	ENSRNOG00000010975

Paralogs (1): ADNP2 (ENSG00000101544)

Protein

Protein identifiers

Activity-dependent neuroprotector homeobox protein — Q9H2P0 (reviewed: Q9H2P0)

Alternative names: Activity-dependent neuroprotective protein

All UniProt accessions (4): Q9H2P0, A0A2R8Y6X0, A0A2R8YCL6, A0A669KBJ7

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in transcriptional regulation. May mediate some of the neuroprotective peptide VIP-associated effects involving normal growth and cancer proliferation. Positively modulates WNT-beta-catenin/CTNN1B signaling, acting by regulating phosphorylation of, and thereby stabilizing, CTNNB1. May be required for neural induction and neuronal differentiation. May be involved in erythroid differentiation.

Subunit / interactions. Interacts (via N-terminal region) with beta-catenin/CTNNB1 (via the central armadillo domains); interaction is direct and stabilizes CTNNB1 by modulating its phosphorylation by glycogen synthase kinase-3 beta GSK3B.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Widely expressed. Strong expression in heart, skeletal muscle, kidney and placenta. In brain, expression is stronger in the cerebellum and cortex regions. No expression detected in the colon. Strong increase of expression in colon and breast cancer tissues.

Disease relevance. Helsmoortel-van der Aa syndrome (HVDAS) [MIM:615873] A disorder characterized by intellectual disability, autism spectrum disorder, and dysmorphic facial features including prominent forehead, high hairline, downslanting palpebral fissures, notched eyelids, broad nasal bridge, thin upper lip, and smooth philtrum. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. When isolated from the sequence, neuroprotective peptide (NAP) provides neuroprotection against the amyloid-beta peptide.

RefSeq proteins (5): NP_001269460, NP_001269461, NP_001334440, NP_056154, NP_852107 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR013087	Znf_C2H2_type	Domain
IPR038861	ADNP/ADNP2	Family
IPR045762	ADNP_Znf	Domain

Pfam: PF00046, PF19627

UniProt features (77 total): cross-link 35, modified residue 19, zinc finger region 9, compositionally biased region 6, region of interest 5, chain 1, DNA-binding region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2P0-F1	57.07	0.06

Functional residue map

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

Post-translational modifications (54): 98, 348, 409, 413, 608, 709, 736, 738, 805, 876, 878, 886, 889, 921, 953, 955, 1035, 1042, 1071, 39 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9940465	ChAHP complex assembly

MSigDB gene sets: 735 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_MEMORY, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GROWTH, GENTILE_RESPONSE_CLUSTER_D3, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY

GO Biological Process (16): regulation of transcription by RNA polymerase II (GO:0006357), short-term memory (GO:0007614), response to carbohydrate (GO:0009743), regulation of gene expression (GO:0010468), negative regulation of gene expression (GO:0010629), positive regulation of neuron projection development (GO:0010976), obsolete cGMP-mediated signaling (GO:0019934), neuron differentiation (GO:0030182), intracellular nitric oxide homeostasis (GO:0033484), negative regulation of neuron apoptotic process (GO:0043524), estrous cycle (GO:0044849), positive regulation of axon extension (GO:0045773), negative regulation of synaptic transmission (GO:0050805), neuron apoptotic process (GO:0051402), positive regulation of synapse assembly (GO:0051965), positive regulation of canonical Wnt signaling pathway (GO:0090263)

GO Molecular Function (11): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), chromatin binding (GO:0003682), copper ion binding (GO:0005507), beta-catenin binding (GO:0008013), zinc ion binding (GO:0008270), peptide binding (GO:0042277), beta-tubulin binding (GO:0048487), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): chromatin (GO:0000785), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), axon (GO:0030424), dendrite (GO:0030425), neuronal cell body (GO:0043025), RNA polymerase II transcription regulator complex (GO:0090575), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
CHD3, CHD4, CHD5 subfamily	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
gene expression	2
transition metal ion binding	2
neuron projection	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
memory	1
response to oxygen-containing compound	1
regulation of macromolecule biosynthetic process	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
cell differentiation	1
generation of neurons	1
intracellular chemical homeostasis	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
ovulation cycle	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
chemical synaptic transmission	1
negative regulation of cell communication	1
negative regulation of signaling	1
modulation of chemical synaptic transmission	1
apoptotic process	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
transcription cis-regulatory region binding	1
chromatin	1

Protein interactions and networks

STRING

1776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADNP	CHD4	Q14839	954
ADNP	ZBTB14	O43829	777
ADNP	GLRX	P35754	713
ADNP	CHD8	Q9HCK8	667
ADNP	KMT5B	Q4FZB7	658
ADNP	SMARCC2	Q8TAQ2	637
ADNP	DYRK1A	Q13627	611
ADNP	ZNF597	Q96LX8	608
ADNP	ARID1A	O14497	606
ADNP	ARID1B	Q8NFD5	581
ADNP	TRIP12	Q14669	543
ADNP	NCKAP1	Q9Y2A7	537
ADNP	MAPRE3	Q9UPY8	533
ADNP	BANF1	O75531	526
ADNP	MAP1LC3B	Q9GZQ8	522

IntAct

151 interactions, top by confidence:

A	B	Type	Score
POLG2	POLG	psi-mi:“MI:0914”(association)	0.950
ADNP	CBX3	psi-mi:“MI:0915”(physical association)	0.850
CBX3	ADNP	psi-mi:“MI:0915”(physical association)	0.850
CBX1	ADNP	psi-mi:“MI:0915”(physical association)	0.770
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ADNP	CBX5	psi-mi:“MI:0915”(physical association)	0.670
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
CBX3	E2F6	psi-mi:“MI:0914”(association)	0.640
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
POLG2	GLDC	psi-mi:“MI:0914”(association)	0.530
ZNF524	C1QBP	psi-mi:“MI:0914”(association)	0.530
ZNF581	DMWD	psi-mi:“MI:0914”(association)	0.530
CBX1	ZNF292	psi-mi:“MI:0914”(association)	0.530
CBX1	KPNA3	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
DAXX	TNRC18	psi-mi:“MI:0914”(association)	0.530

BioGRID (301): ADNP (Protein-peptide), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS), ADNP (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GR68, A2CG63, E9Q9M8, F7AQ22, G3V8T1, O75152, O75376, P49140, P51826, P97432, Q13625, Q14596, Q17R98, Q1LY51, Q3TYA6, Q4KKX4, Q4LE39, Q4R6F6, Q501R9, Q505G8, Q5F3Z9, Q5HYC2, Q5RC94, Q5XJV7, Q60974, Q68FE8, Q69Z61, Q6A098, Q6NXK2, Q6NZF1, Q6PJT7, Q6ZNC4, Q86YI8, Q8BFU3, Q8BJ05, Q8CCH7, Q8CG79, Q8CHY6, Q8K2W6, Q8ND24

Diamond homologs: F1QLG5, Q6IQ32, Q9H2P0, Q9JKL8, Q9Z103

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ADNP	“up-regulates quantity by stabilization”	CTNNB1	binding
ADNP	“up-regulates quantity”	“SWI/SNF complex”	binding
ADNP	“form complex”	ChAHP	binding
ADNP	“down-regulates activity”	CTCF	relocalization
ADNP	up-regulates	Neurogenesis
ADNP	“up-regulates activity”	MAP1LC3B	binding
ADNP	“up-regulates quantity by expression”	BECN1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 184 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Notch-HLH transcription pathway	5	16.7×	2e-03
NOTCH1 Intracellular Domain Regulates Transcription	6	11.7×	2e-03
NS1 Mediated Effects on Host Pathways	5	11.7×	5e-03
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	9	10.8×	9e-05
Constitutive Signaling by NOTCH1 PEST Domain Mutants	6	9.7×	3e-03
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	6	9.7×	3e-03
Influenza Infection	6	8.6×	5e-03
ISG15 antiviral mechanism	6	7.4×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
NLS-bearing protein import into nucleus	5	24.6×	5e-04
heterochromatin formation	6	9.4×	7e-03
RNA splicing	10	5.4×	4e-03
DNA damage response	12	3.9×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	117
Likely pathogenic	49
Uncertain significance	394
Likely benign	212
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1174075	NM_001282531.3(ADNP):c.898dup (p.Ser300fs)	Pathogenic
1184924	NM_001282531.3(ADNP):c.1807_1808dup (p.Pro604fs)	Pathogenic
1299548	NM_001282531.3(ADNP):c.655_656del (p.Glu218_Ser219insTer)	Pathogenic
1334645	NM_001282531.3(ADNP):c.2454C>G (p.Tyr818Ter)	Pathogenic
1335928	NM_001282531.3(ADNP):c.69dup (p.Ser24Ter)	Pathogenic
1338860	NM_001282531.3(ADNP):c.2387G>A (p.Trp796Ter)	Pathogenic
139632	NM_001282531.3(ADNP):c.2496_2499del (p.Asn832fs)	Pathogenic
139633	NM_001282531.3(ADNP):c.1211C>A (p.Ser404Ter)	Pathogenic
139634	NM_001282531.3(ADNP):c.2808del (p.Lys935_Tyr936insTer)	Pathogenic
139635	NM_001282531.3(ADNP):c.2157C>G (p.Tyr719Ter)	Pathogenic
1456498	NC_000020.10:g.(?49354394)(49626875_?)del	Pathogenic
1527880	NM_001282531.3(ADNP):c.2167del (p.Glu723fs)	Pathogenic
1527885	NM_001282531.3(ADNP):c.2495_2499del (p.Asn832fs)	Pathogenic
1684264	NM_001282531.3(ADNP):c.95_96insT (p.Lys32fs)	Pathogenic
1685506	NM_001282531.3(ADNP):c.2424_2427del (p.Lys809fs)	Pathogenic
1693315	NM_001282531.3(ADNP):c.2630_2633del (p.Asp877fs)	Pathogenic
1698716	NM_001282531.3(ADNP):c.2155del (p.Tyr719fs)	Pathogenic
1709398	NM_001282531.3(ADNP):c.2292T>G (p.Tyr764Ter)	Pathogenic
1712218	NM_001282531.3(ADNP):c.83dup (p.Leu28fs)	Pathogenic
1804918	NM_001282531.3(ADNP):c.2212dup (p.Ser738fs)	Pathogenic
1805170	NM_001282531.3(ADNP):c.2483dup (p.Met828fs)	Pathogenic
2002784	NM_001282531.3(ADNP):c.35T>A (p.Leu12Ter)	Pathogenic
2018222	NM_001282531.3(ADNP):c.2305del (p.Ser769fs)	Pathogenic
2026497	NM_001282531.3(ADNP):c.1929dup (p.Arg644fs)	Pathogenic
2029776	NM_001282531.3(ADNP):c.1401_1404del (p.Lys467fs)	Pathogenic
2138355	NM_001282531.3(ADNP):c.1A>G (p.Met1Val)	Pathogenic
2429490	NM_001282531.3(ADNP):c.14del (p.Pro5fs)	Pathogenic
2442385	NM_001282531.3(ADNP):c.1191dup (p.Asn398Ter)	Pathogenic
265590	NM_001282531.3(ADNP):c.1106_1108delinsCTGT (p.Leu369fs)	Pathogenic
2759035	NM_001282531.3(ADNP):c.2103_2106dup (p.Pro703fs)	Pathogenic

SpliceAI

931 predictions. Top by Δscore:

Variant	Effect	Δscore
20:50903881:CTACT:C	donor_loss	1.0000
20:50903882:TACTT:T	donor_loss	1.0000
20:50903883:ACTTA:A	donor_loss	1.0000
20:50903884:CT:C	donor_loss	1.0000
20:50903885:TTACT:T	donor_loss	1.0000
20:50903886:T:TG	donor_loss	1.0000
20:50903887:A:AC	donor_gain	1.0000
20:50903887:A:T	donor_loss	1.0000
20:50903887:ACTT:A	donor_gain	1.0000
20:50903888:C:CA	donor_gain	1.0000
20:50903888:CT:C	donor_gain	1.0000
20:50903888:CTT:C	donor_gain	1.0000
20:50903888:CTTC:C	donor_gain	1.0000
20:50903997:AGTTT:A	acceptor_gain	1.0000
20:50903998:GTTT:G	acceptor_gain	1.0000
20:50903999:TTT:T	acceptor_gain	1.0000
20:50904000:TT:T	acceptor_gain	1.0000
20:50904000:TTC:T	acceptor_loss	1.0000
20:50904001:TCTA:T	acceptor_loss	1.0000
20:50904002:C:CC	acceptor_gain	1.0000
20:50904003:T:C	acceptor_loss	1.0000
20:50904005:T:TC	acceptor_gain	1.0000
20:50930821:CTTA:C	donor_loss	1.0000
20:50930822:TTA:T	donor_loss	1.0000
20:50930823:TA:T	donor_loss	1.0000
20:50930824:ACC:A	donor_loss	1.0000
20:50903888:CTTCT:C	donor_gain	0.9900
20:50904005:T:C	acceptor_gain	0.9900
20:50904852:T:C	acceptor_gain	0.9900
20:50930820:GCTTA:G	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000049736 (20:50898461 A>G), RS1000087161 (20:50930003 A>G,T), RS1000140357 (20:50931881 G>A,C), RS1000165315 (20:50898704 G>T), RS1000194579 (20:50890017 T>C), RS1000270002 (20:50929373 T>C,G), RS1000406225 (20:50929625 C>T), RS1000436601 (20:50904519 A>C,G,T), RS1000504367 (20:50915485 C>T), RS1000510493 (20:50888614 C>G), RS1000551412 (20:50899915 A>C), RS1000612318 (20:50894881 G>C), RS1000726376 (20:50895243 C>A,G), RS1000739609 (20:50930514 C>G), RS1000790079 (20:50888948 T>C)

Disease associations

OMIM: gene MIM:611386 | disease phenotypes: MIM:615873, MIM:217990, MIM:608799

GenCC curated gene-disease

Disease	Classification	Inheritance
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	Definitive	AD

Mondo (9): ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (MONDO:0014379), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), stereotypic movement disorder (MONDO:0002265), hypothyroidism (MONDO:0005420), corpus callosum, agenesis of (MONDO:0009022), congenital disorder of glycosylation type 1E (MONDO:0012123), microcephaly (MONDO:0001149), autism spectrum disorder (MONDO:0005258)

Orphanet (5): Helsmoortel-Van der Aa syndrome (Orphanet:404448), Isolated corpus callosum agenesis (Orphanet:200), DPM1-CDG (Orphanet:79322), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

168 total (30 of 168 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000020	Urinary incontinence
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000105	Enlarged kidney
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000233	Thin vermilion border
HP:0000243	Trigonocephaly
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000283	Broad face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000331	Short chin
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000483	Astigmatism

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002606_23	Prostate cancer	2.000000e-07
GCST002606_5	Prostate cancer	5.000000e-11

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D061085	Agenesis of Corpus Callosum	C10.500.034; C16.131.666.034; C23.300.008
D007037	Hypothyroidism	C19.874.482
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D019956	Stereotypic Movement Disorder	F03.625.984
C535743	Congenital disorder of glycosylation type 1E (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation	10
sodium arsenite	affects binding, increases reaction, decreases expression, increases abundance	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Formaldehyde	decreases expression	2
Aflatoxin B1	increases expression, decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
uranyl acetate	affects expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	decreases expression, increases abundance	1

Cellosaurus cell lines

5 cell lines: 2 induced pluripotent stem cell, 1 transformed cell line, 1 finite cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6XY	GM28570	Transformed cell line	Male
CVCL_D6XZ	GM28572	Finite cell line	Male
CVCL_D6Z5	GM28947	Induced pluripotent stem cell	Male
CVCL_GZ75	K562 eGFP-ADNP	Cancer cell line	Female
CVCL_WM08	GENYOi004-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

199 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)
NCT04388774	PHASE1/PHASE2	COMPLETED	Low-Dose Ketamine in Children With ADNP Syndrome
NCT03718936	Not specified	RECRUITING	ADNP Syndrome: The Seaver Autism Center for Research and Treatment is Characterizing ADNP-related Neurodevelopmental Disorders Using Genetic, Medical, and Neuropsychological Measures.
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