HIVEP2

Summary

HIVEP2 (HIVEP zinc finger 2, HGNC:4921) is a protein-coding gene on chromosome 6q24.2, encoding Transcription factor HIVEP2 (P31629). This protein specifically binds to the DNA sequence 5’-GGGACTTTCC-3’ which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV1. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of a family of closely related, large, zinc finger-containing transcription factors. The encoded protein regulates transcription by binding to regulatory regions of various cellular and viral genes that maybe involved in growth, development and metastasis. The protein contains the ZAS domain comprised of two widely separated regions of zinc finger motifs, a stretch of highly acidic amino acids and a serine/threonine-rich sequence.

Source: NCBI Gene 3097 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal dominant 43 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 19
• Clinical variants (ClinVar): 1,466 total — 54 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 122
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 12 downstream targets (CollecTRI)
• MANE Select transcript: NM_006734

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4921
Approved symbol	HIVEP2
Name	HIVEP zinc finger 2
Location	6q24.2
Locus type	gene with protein product
Status	Approved
Aliases	MBP-2, HIV-EP2, MIBP1, ZAS2, Schnurri-2, ZNF40B
Ensembl gene	ENSG00000010818
Ensembl biotype	protein_coding
OMIM	143054
Entrez	3097

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 15 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000012134, ENST00000367603, ENST00000367604, ENST00000421237, ENST00000474532, ENST00000703916, ENST00000703917, ENST00000703918, ENST00000703919, ENST00000703920, ENST00000859142, ENST00000932991, ENST00000932992, ENST00000932993, ENST00000932994, ENST00000949342

RefSeq mRNA: 1 — MANE Select: NM_006734 NM_006734

CCDS: CCDS43510

Canonical transcript exons

ENST00000367603 — 10 exons

Exon	Start	End
ENSE00000764841	142768382	142768536
ENSE00000764843	142764799	142764974
ENSE00000764844	142761464	142761565
ENSE00000764845	142759772	142760667
ENSE00000798981	142751469	142753931
ENSE00001445111	142769552	142775125
ENSE00001445112	142945099	142945176
ENSE00001445146	142776147	142776191
ENSE00001445147	142783521	142783615
ENSE00001445148	142836935	142837047

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.8606 / max 978.6060, expressed in 1742 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76026	14.5336	1629
76018	7.1629	1438
76023	3.3088	1323
76025	1.0694	505
76022	0.9702	442
76029	0.8666	218
76017	0.8084	279
76028	0.7952	353
76027	0.3253	153
76024	0.2925	140

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	98.40	gold quality
vena cava	UBERON:0004087	98.23	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.04	gold quality
saphenous vein	UBERON:0007318	97.62	gold quality
frontal pole	UBERON:0002795	97.54	gold quality
synovial joint	UBERON:0002217	97.28	gold quality
pons	UBERON:0000988	97.01	gold quality
cerebellar vermis	UBERON:0004720	96.62	gold quality
body of tongue	UBERON:0011876	96.57	gold quality
endothelial cell	CL:0000115	96.35	gold quality
cortical plate	UBERON:0005343	96.33	gold quality
paraflocculus	UBERON:0005351	96.31	gold quality
lateral globus pallidus	UBERON:0002476	96.30	gold quality
superior surface of tongue	UBERON:0007371	95.97	gold quality
ventral tegmental area	UBERON:0002691	95.90	gold quality
nipple	UBERON:0002030	95.78	gold quality
tongue	UBERON:0001723	95.71	gold quality
superior vestibular nucleus	UBERON:0007227	95.52	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.24	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.17	gold quality
type B pancreatic cell	CL:0000169	95.16	gold quality
occipital lobe	UBERON:0002021	95.10	gold quality
pericardium	UBERON:0002407	94.95	gold quality
substantia nigra pars compacta	UBERON:0001965	94.77	gold quality
middle temporal gyrus	UBERON:0002771	94.76	gold quality
cervix squamous epithelium	UBERON:0006922	94.74	gold quality
medulla oblongata	UBERON:0001896	94.68	gold quality
parotid gland	UBERON:0001831	94.53	gold quality
mucosa of urinary bladder	UBERON:0001259	94.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.71
E-MTAB-2983	no	242.14

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

12 targets.

Target	Regulation
BGLAP	Activation
HLA-A	Unknown
HLA-B	Unknown
HLA-C	Unknown
HLA-E	Unknown
HLA-F	Unknown
HLA-G	Unknown
MYC	Repression
NFKB
PPARG	Activation
SP7	Activation
SSTR2	Activation

miRNA regulators (miRDB)

212 targeting HIVEP2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5688	99.96	73.23	4504

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• The primary effect of MIBP1 (also known as HIVEP2) is the downregulation of the NF-kappaB pathway, and this effect is attenuated by O-GlcNAc signaling. (PMID:22294689)
• a 154-amino acid region of MIBP1 was necessary for its O-GlcNAc transferase binding and O-GlcNAcylation. (PMID:22294689)
• HIVEP2 loss-of-function mutations were identified in intellectual disability patients. (PMID:26153216)
• Study provide further evidence that pathogenic variants in Human immunodeficiency virus type I enhancer binding protein 2 lead to intellectual disabilities and developmental delay. (PMID:27003583)
• human miR-186, 210 and 222 directly regulate the human genes Dicer1, HRB and HIV-EP2, thus may be filling key roles during HIV-1 replication and miRNA biogenesis. (PMID:30682089)
• We describe the phenotype and genotype of two additional patients with novel de novo pathogenic HIVEP2 variants, who have previously unreported features, including hyperphagia and Angelman-like features. (PMID:31207095)
• HIVEP2-mediated transcriptional mechanisms are implicated in dopaminergic pathophysiology of substance use disorder. (PMID:31586043)
• Nuclear factor kappa B activation appears weaker in schizophrenia patients with high brain cytokines than in non-schizophrenic controls with high brain cytokines. (PMID:32680547)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hivep2a	ENSDARG00000039987
mus_musculus	Hivep2	ENSMUSG00000015501
rattus_norvegicus	Hivep2	ENSRNOG00000011015

Paralogs (14): HIVEP1 (ENSG00000095951), SALL4 (ENSG00000101115), ZNF516 (ENSG00000101493), SALL1 (ENSG00000103449), BCL11A (ENSG00000119866), ZNF831 (ENSG00000124203), RREB1 (ENSG00000124782), HIVEP3 (ENSG00000127124), BCL11B (ENSG00000127152), ZNF219 (ENSG00000165804), SALL2 (ENSG00000165821), ZNF217 (ENSG00000171940), ZNF536 (ENSG00000198597), SALL3 (ENSG00000256463)

Protein

Protein identifiers

Transcription factor HIVEP2 — P31629 (reviewed: P31629)

Alternative names: Human immunodeficiency virus type I enhancer-binding protein 2, MHC-binding protein 2

All UniProt accessions (5): P31629, A0A994J411, A0A994J481, A0A994J6P4, A0A994J742

UniProt curated annotations — full annotation on UniProt →

Function. This protein specifically binds to the DNA sequence 5’-GGGACTTTCC-3’ which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV1. In addition, related sequences are found in the enhancer elements of a number of cellular promoters, including those of the class I MHC, interleukin-2 receptor, somatostatin receptor II, and interferon-beta genes. It may act in T-cell activation.

Subunit / interactions. Interacts with TCF4.

Subcellular location. Nucleus.

Tissue specificity. Expressed in brain and skeletal muscle.

Disease relevance. Intellectual developmental disorder, autosomal dominant 43 (MRD43) [MIM:616977] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD43 patients manifest developmental delay, intellectual disability, hypotonia, and dysmorphic features. The disease is caused by variants affecting the gene represented in this entry.

Induction. By mitogens and phorbol ester.

RefSeq proteins (1): NP_006725* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR051969

Pfam: PF00096

UniProt features (62 total): compositionally biased region 18, region of interest 12, modified residue 11, repeat 10, zinc finger region 4, sequence variant 4, chain 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31629-F1	36.43	0.03

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 (11): 819, 950, 955, 1048, 1443, 1447, 2118, 2297, 2301, 2429, 2431

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 447 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, MODULE_255, TGCACTT_MIR519C_MIR519B_MIR519A, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MODULE_317, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, TATTATA_MIR374, GTGCCTT_MIR506, CAIRO_HEPATOBLASTOMA_CLASSES_DN, FOSTER_TOLERANT_MACROPHAGE_UP, ATTACAT_MIR3803P, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, ACATTCC_MIR1_MIR206, AGGAGTG_MIR483

GO Biological Process (1): regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (2): nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transition metal ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1396 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIVEP2	CLIC4	Q9Y696	896
HIVEP2	SSTR2	P30874	702
HIVEP2	PPM1A	P35813	697
HIVEP2	TCF4	P15884	668
HIVEP2	SMAD4	Q13485	658
HIVEP2	CEBPA	P49715	630
HIVEP2	SLC16A8	O95907	548
HIVEP2	HRH3	Q9Y5N1	548
HIVEP2	SMAD2	Q15796	522
HIVEP2	NFKB1	P19838	512
HIVEP2	SSTR4	P31391	497
HIVEP2	AQP1	P29972	495
HIVEP2	SMAD3	P84022	491
HIVEP2	GTF2A1	P52655	490
HIVEP2	AIG1	Q9NVV5	441

IntAct

47 interactions, top by confidence:

A	B	Type	Score
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
FBXW11	AHCYL1	psi-mi:“MI:0914”(association)	0.530
HIVEP2		psi-mi:“MI:0915”(physical association)	0.490
	HIVEP2	psi-mi:“MI:0915”(physical association)	0.490
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
	HIVEP2	psi-mi:“MI:0915”(physical association)	0.370
BTRC	ACOT7	psi-mi:“MI:0914”(association)	0.350
FBXW11	PTCD1	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350
BTRC	OGT	psi-mi:“MI:0914”(association)	0.350
FBXW11	OGT	psi-mi:“MI:0914”(association)	0.350
CAMK2G	PSMD12	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAQ	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
NUP62CL	WASH3P	psi-mi:“MI:0914”(association)	0.350
YWHAZ	HECTD4	psi-mi:“MI:0914”(association)	0.350
SKP1	BHLHE40	psi-mi:“MI:0914”(association)	0.350
TRIM9	GFAP	psi-mi:“MI:0914”(association)	0.350
FBXW11	BHLHE40	psi-mi:“MI:0914”(association)	0.350
BTRC	BHLHE40	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
FBXW11	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
SKP1	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
OGT	SMCHD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): HIVEP2 (Affinity Capture-MS), HIVEP2 (Affinity Capture-MS), HIVEP2 (Affinity Capture-MS), HIVEP2 (Affinity Capture-MS), HIVEP2 (Affinity Capture-MS), HIVEP2 (Affinity Capture-MS), HIVEP2 (Two-hybrid), HIVEP2 (Affinity Capture-RNA), HIVEP2 (Affinity Capture-MS), HIVEP2 (Affinity Capture-RNA), HIVEP2 (Protein-RNA), HIVEP2 (Two-hybrid), HIVEP2 (Affinity Capture-MS), HIVEP2 (Affinity Capture-MS), HIVEP2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GSA2, A0A1L8H0H2, A0JP82, A0MS83, A2AWL7, A2RRX6, A6NCI8, F8VPJ6, K9JHZ4, O13186, O46567, O60284, O75362, P15822, P31629, P35547, P37275, P48552, P79269, P79686, Q03172, Q14207, Q28DZ0, Q2KHR2, Q3U285, Q3V0A6, Q3Y4E1, Q4JK59, Q4V7H1, Q4V7J0, Q5R782, Q5W1J6, Q5ZJK5, Q60988, Q61624, Q62806, Q6N021, Q6XLJ0, Q80TY4, Q8BMA5

Diamond homologs: A1L2U9, A2A884, A2ANX9, A7Y7X5, B0X9H6, B0YDH7, B1WAZ8, B1WBU4, O35615, O62836, O77459, P08048, P10925, P15822, P17010, P17012, P20662, P31505, P31629, P60319, P78871, P80944, Q00900, Q01611, Q02031, Q03172, Q0IH98, Q0VCJ6, Q292R5, Q29419, Q3UHF7, Q52V16, Q5JPB2, Q5T1R4, Q6B4Z5, Q7JM44, Q811F1, Q86UZ6, Q8BID6, Q8CII0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HIVEP2	“up-regulates quantity by expression”	SSTR2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 42 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
Activation of BAD and translocation to mitochondria	6	169.2×	8e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	149.3×	1e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	149.3×	1e-10
Activation of BH3-only proteins	6	110.3×	7e-10
RHO GTPases activate PKNs	6	70.5×	9e-09
Intrinsic Pathway for Apoptosis	6	65.1×	1e-08
SARS-CoV-1-host interactions	6	39.0×	3e-07
Apoptosis	6	37.3×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	52.3×	1e-05
intracellular protein localization	6	17.9×	1e-04
protein ubiquitination	6	7.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1466 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	54
Likely pathogenic	22
Uncertain significance	637
Likely benign	462
Benign	154

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1184547	NM_006734.4(HIVEP2):c.2853_2854del (p.Glu953fs)	Pathogenic
1298289	NM_006734.4(HIVEP2):c.5890G>T (p.Gly1964Ter)	Pathogenic
1685875	NM_006734.4(HIVEP2):c.5791dup (p.Thr1931fs)	Pathogenic
1700005	NM_006734.4(HIVEP2):c.5856dup (p.Val1953fs)	Pathogenic
1700094	NM_006734.4(HIVEP2):c.476_477del (p.Asn159fs)	Pathogenic
1995920	NM_006734.4(HIVEP2):c.2931_2932del (p.Ser978fs)	Pathogenic
2121683	NM_006734.4(HIVEP2):c.3042C>A (p.Tyr1014Ter)	Pathogenic
2126134	NM_006734.4(HIVEP2):c.365_380del (p.Pro122fs)	Pathogenic
224791	NM_006734.4(HIVEP2):c.2827C>T (p.Arg943Ter)	Pathogenic
224792	NM_006734.4(HIVEP2):c.2905C>T (p.Gln969Ter)	Pathogenic
224793	NM_006734.4(HIVEP2):c.6475G>T (p.Gly2159Ter)	Pathogenic
224794	NM_006734.4(HIVEP2):c.2857G>T (p.Glu953Ter)	Pathogenic
224795	NM_006734.4(HIVEP2):c.5614dup (p.Glu1872fs)	Pathogenic
224798	NM_006734.4(HIVEP2):c.1189G>T (p.Asp397Tyr)	Pathogenic
236210	NM_006734.4(HIVEP2):c.5737del (p.Asp1913fs)	Pathogenic
236212	NM_006734.4(HIVEP2):c.3556C>T (p.Gln1186Ter)	Pathogenic
2626990	NM_006734.4(HIVEP2):c.868G>T (p.Glu290Ter)	Pathogenic
2745471	NM_006734.4(HIVEP2):c.1362_1369del (p.Ile455fs)	Pathogenic
2815620	NM_006734.4(HIVEP2):c.4793_4806del (p.Gly1598fs)	Pathogenic
2817292	NM_006734.4(HIVEP2):c.4525C>T (p.Gln1509Ter)	Pathogenic
3024316	NM_006734.4(HIVEP2):c.5653A>T (p.Lys1885Ter)	Pathogenic
3062061	NM_006734.4(HIVEP2):c.5764del (p.Asp1922fs)	Pathogenic
3106051	NM_006734.4(HIVEP2):c.3469C>T (p.Gln1157Ter)	Pathogenic
3234788	NM_006734.4(HIVEP2):c.5798C>G (p.Ser1933Ter)	Pathogenic
3236242	NM_006734.4(HIVEP2):c.3412C>T (p.Gln1138Ter)	Pathogenic
3284378	NM_006734.4(HIVEP2):c.6655C>T (p.Gln2219Ter)	Pathogenic
3336894	NM_006734.4(HIVEP2):c.5110del (p.Ile1704fs)	Pathogenic
3342115	NM_006734.4(HIVEP2):c.2289_2296dup (p.Gln766fs)	Pathogenic
3382760	NM_006734.4(HIVEP2):c.5994C>G (p.Tyr1998Ter)	Pathogenic
3643539	NM_006734.4(HIVEP2):c.5643dup (p.Ala1882fs)	Pathogenic

SpliceAI

1739 predictions. Top by Δscore:

Variant	Effect	Δscore
6:142753927:AAATT:A	acceptor_gain	1.0000
6:142753929:ATTC:A	acceptor_loss	1.0000
6:142753930:TT:T	acceptor_gain	1.0000
6:142753930:TTCTG:T	acceptor_loss	1.0000
6:142753931:TCT:T	acceptor_loss	1.0000
6:142753932:C:CC	acceptor_gain	1.0000
6:142753932:CT:C	acceptor_loss	1.0000
6:142753933:T:C	acceptor_loss	1.0000
6:142760664:TTTT:T	acceptor_gain	1.0000
6:142760665:TTT:T	acceptor_gain	1.0000
6:142760666:TTCTG:T	acceptor_loss	1.0000
6:142760668:C:CC	acceptor_gain	1.0000
6:142760668:CTGA:C	acceptor_loss	1.0000
6:142760674:C:CT	acceptor_gain	1.0000
6:142760675:A:T	acceptor_gain	1.0000
6:142760677:T:C	acceptor_gain	1.0000
6:142760677:T:TC	acceptor_gain	1.0000
6:142761463:C:A	donor_loss	1.0000
6:142761463:CCTG:C	donor_gain	1.0000
6:142761469:T:TA	donor_gain	1.0000
6:142761562:TTTC:T	acceptor_gain	1.0000
6:142761564:TCC:T	acceptor_loss	1.0000
6:142761565:CCT:C	acceptor_gain	1.0000
6:142761566:C:CA	acceptor_loss	1.0000
6:142761566:C:CC	acceptor_gain	1.0000
6:142761567:T:C	acceptor_gain	1.0000
6:142761567:T:TC	acceptor_gain	1.0000
6:142761573:A:AC	acceptor_gain	1.0000
6:142761573:A:C	acceptor_gain	1.0000
6:142761575:G:GC	acceptor_gain	1.0000

AlphaMissense

16044 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:142761519:G:C	C1855W	1.000
6:142761520:C:G	C1855S	1.000
6:142761521:A:G	C1855R	1.000
6:142761521:A:T	C1855S	1.000
6:142761531:G:C	H1851Q	1.000
6:142761531:G:T	H1851Q	1.000
6:142761532:T:C	H1851R	1.000
6:142761533:G:C	H1851D	1.000
6:142761538:T:A	K1849I	1.000
6:142761541:G:A	S1848F	1.000
6:142761542:A:G	S1848P	1.000
6:142761543:T:A	K1847N	1.000
6:142761543:T:G	K1847N	1.000
6:142761545:T:C	K1847E	1.000
6:142761549:A:C	H1845Q	1.000
6:142761549:A:T	H1845Q	1.000
6:142761550:T:C	H1845R	1.000
6:142761550:T:G	H1845P	1.000
6:142761551:G:A	H1845Y	1.000
6:142761551:G:C	H1845D	1.000
6:142761551:G:T	H1845N	1.000
6:142761552:C:A	K1844N	1.000
6:142761552:C:G	K1844N	1.000
6:142761553:T:A	K1844M	1.000
6:142761554:T:C	K1844E	1.000
6:142761554:T:G	K1844Q	1.000
6:142761559:A:G	L1842P	1.000
6:142761559:A:T	L1842Q	1.000
6:142761561:G:C	N1841K	1.000
6:142761561:G:T	N1841K	1.000

dbSNP variants (sampled 300 via entrez): RS1000020263 (6:142780876 A>T), RS1000032069 (6:142868696 T>C), RS1000046845 (6:142763023 C>T), RS1000048930 (6:142841634 C>T), RS1000088972 (6:142918208 T>C), RS1000102910 (6:142797134 C>A,G), RS1000107428 (6:142944369 C>A,G,T), RS1000114692 (6:142800075 T>A,G), RS1000115077 (6:142813619 G>A), RS1000146580 (6:142857047 C>T), RS1000177460 (6:142788170 C>T), RS1000205067 (6:142850297 G>A), RS1000220996 (6:142936952 A>G), RS1000223392 (6:142844210 G>A,C,T), RS1000226964 (6:142804056 C>G,T)

Disease associations

OMIM: gene MIM:143054 | disease phenotypes: MIM:616977, MIM:614563, MIM:613107

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 43	Definitive	Autosomal dominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant

Mondo (10): intellectual disability, autosomal dominant 43 (MONDO:0014858), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), intellectual disability, autosomal dominant 13 (MONDO:0013805), coloboma (MONDO:0001476), vascular disorder (MONDO:0005385), neutropenia, severe congenital, 2, autosomal dominant (MONDO:0013139), epilepsy (MONDO:0005027), neurodevelopmental disorder (MONDO:0700092), autosomal dominant non-syndromic intellectual disability (MONDO:0015802)

Orphanet (4): OBSOLETE: Ocular coloboma (Orphanet:194), Autosomal dominant severe congenital neutropenia (Orphanet:486), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

122 total (30 of 122 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000225	Gingival bleeding
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000321	Square face
HP:0000322	Short philtrum
HP:0000331	Short chin
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000348	High forehead
HP:0000391	Thickened helices
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000540	Hypermetropia

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002233_3	Adiponectin levels	6.000000e-06
GCST002358_7	Pit-and-Fissure caries	4.000000e-06
GCST003518_87	Daytime sleep phenotypes	1.000000e-06
GCST005194_200	Coronary artery disease	1.000000e-06
GCST008103_101	Bipolar disorder	3.000000e-06
GCST008152_41	Weight	5.000000e-07
GCST008357_16	Mood instability	4.000000e-09
GCST009860_2	IgG N-glycosylation phenotypes (multivariate analysis)	1.000000e-13
GCST010039_1	Adverse response to inhaled corticosteroid treatment x age interaction in asthma	5.000000e-08
GCST010043_149	Asthma	2.000000e-09
GCST010118_143	Type 2 diabetes	6.000000e-09
GCST010242_358	HDL cholesterol levels	1.000000e-10
GCST010988_378	Adult body size	3.000000e-10
GCST90000050_55	Age at first birth	1.000000e-08
GCST90000514_8	Gastroesophageal reflux disease	4.000000e-09
GCST90002381_165	Eosinophil count	3.000000e-09
GCST90002382_356	Eosinophil percentage of white cells	3.000000e-09
GCST90002384_54	Hemoglobin	1.000000e-09
GCST90002401_539	Platelet distribution width	3.000000e-13

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004502	adiponectin measurement
EFO:0007828	daytime rest measurement
EFO:0004338	body weight
EFO:0008475	mood instability measurement
EFO:0005193	serum IgG glycosylation measurement
EFO:0008007	age at assessment
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009101	age at first birth measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004509	hemoglobin measurement
EFO:0007984	platelet component distribution width

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D014652	Vascular Diseases	C14.907
C567748	Neutropenia, Severe Congenital, Autosomal Dominant 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523214 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	3
Cyclosporine	increases expression	3
Asbestos, Crocidolite	affects expression, increases expression	3
sodium arsenite	decreases expression, increases abundance	2
entinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Cisplatin	decreases expression, increases expression, affects cotreatment	2
Ethinyl Estradiol	affects expression, decreases expression	2
Formaldehyde	decreases expression	2
Silicon Dioxide	increases expression	2
Tretinoin	increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
ethylbenzene	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
nickel chloride	increases expression	1
manganese chloride	decreases expression, increases abundance	1
2-xylene	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4412654	Binding	Inhibition of MBP2 (unknown origin) at 10 uM after 60 mins by ADP-Glo luminescence assay	Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis. — Eur J Med Chem

Clinical trials (associated diseases)

299 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
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)