MBD5

Summary

MBD5 (methyl-CpG binding domain protein 5, HGNC:20444) is a protein-coding gene on chromosome 2q23.1, encoding Methyl-CpG-binding domain protein 5 (Q9P267). Non-catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at ‘Lys-120’ (H2AK119ub1). It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined.

Source: NCBI Gene 55777 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 1,881 total — 119 pathogenic, 45 likely-pathogenic
• Phenotypes (HPO): 96
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001378120

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20444
Approved symbol	MBD5
Name	methyl-CpG binding domain protein 5
Location	2q23.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11113, KIAA1461
Ensembl gene	ENSG00000204406
Ensembl biotype	protein_coding
OMIM	611472
Entrez	55777

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 23 protein_coding_CDS_not_defined, 7 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000407073, ENST00000416015, ENST00000469438, ENST00000470063, ENST00000473478, ENST00000478190, ENST00000478804, ENST00000488372, ENST00000496158, ENST00000496893, ENST00000627651, ENST00000628572, ENST00000629878, ENST00000630352, ENST00000635796, ENST00000636371, ENST00000636620, ENST00000636948, ENST00000637067, ENST00000637159, ENST00000637242, ENST00000637308, ENST00000637316, ENST00000637445, ENST00000637502, ENST00000637830, ENST00000637835, ENST00000637850, ENST00000637997, ENST00000638043, ENST00000638090, ENST00000638130, ENST00000642680

RefSeq mRNA: 2 — MANE Select: NM_001378120 NM_001378120, NM_018328

CCDS: CCDS33302, CCDS92873

Canonical transcript exons

ENST00000642680 — 14 exons

Exon	Start	End
ENSE00001468262	148485742	148485950
ENSE00001468265	148468341	148470461
ENSE00001468266	148463739	148463919
ENSE00001468268	148462582	148462684
ENSE00001549873	148458203	148458871
ENSE00001551453	148483110	148484135
ENSE00001551506	148233245	148233395
ENSE00001553791	148342214	148342336
ENSE00001562360	148178700	148178793
ENSE00001599850	148512870	148516971
ENSE00003490297	148502436	148502509
ENSE00003506367	148510060	148510135
ENSE00003616927	148489386	148490594
ENSE00003899604	148021091	148021684

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 96.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.2362 / max 405.6740, expressed in 1812 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22948	13.9496	1775
22947	7.8525	1755
22950	3.9572	1076
22946	2.6003	1126
22951	0.5005	258
22949	0.3761	200

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	96.67	gold quality
adrenal tissue	UBERON:0018303	96.25	gold quality
sural nerve	UBERON:0015488	95.40	gold quality
colonic epithelium	UBERON:0000397	94.24	gold quality
cortical plate	UBERON:0005343	89.59	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.62	gold quality
corpus callosum	UBERON:0002336	86.59	gold quality
left testis	UBERON:0004533	86.58	gold quality
stromal cell of endometrium	CL:0002255	86.38	gold quality
right testis	UBERON:0004534	86.10	gold quality
granulocyte	CL:0000094	85.45	gold quality
left ovary	UBERON:0002119	85.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.39	gold quality
right coronary artery	UBERON:0001625	84.94	gold quality
ganglionic eminence	UBERON:0004023	84.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.85	gold quality
testis	UBERON:0000473	84.74	gold quality
ventricular zone	UBERON:0003053	84.63	gold quality
popliteal artery	UBERON:0002250	84.53	gold quality
tibial artery	UBERON:0007610	84.49	gold quality
lower esophagus	UBERON:0013473	84.28	gold quality
gall bladder	UBERON:0002110	84.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.27	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.91	gold quality
monocyte	CL:0000576	83.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.83	gold quality
right ovary	UBERON:0002118	83.73	gold quality
leukocyte	CL:0000738	83.68	gold quality
aorta	UBERON:0000947	83.68	gold quality
muscle of leg	UBERON:0001383	83.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.20

Regulation

Is transcription factor: no

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 20)

• Haploinsufficiency of MBD5 is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures.( (PMID:19904302)
• MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. (PMID:20700456)
• 2q23 de novo microdeletion involving the MBD5 gene in a patient with developmental delay, postnatal microcephaly and distinct facial features. (PMID:21271666)
• MBD5 is a single causal locus as shown by 2q23.1 microdeletion syndrome with roles in intellectual disability, epilepsy, and autism spectrum disorder (PMID:21981781)
• MBD5 was tied to neurodevelopmental disorders following the identification of microdeletions on chromosome 2q22-2q23. (PMID:23055267)
• Identified de novo intragenic deletions of MBD5 in three patients. (PMID:23422940)
• study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. (PMID:23587880)
• The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development. (PMID:23632792)
• We studied and showed that both MBD5 and MBD6 interact with the mammalian PR-DUB Polycomb protein complex in a mutually exclusive manner, and that the MBD of MBD5 and MBD6 is both necessary and sufficient to mediate this interaction. (PMID:24634419)
• A genomic copy number variant analysis implicates the MBD5 and HNRNPU genes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion. (PMID:24885232)
• Circadian rhythm gene expression altered by haploinsufficiency of MBD5. (PMID:25271084)
• Results show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. (PMID:25853262)
• Reduced MBD5 dosage leads to mRNA and microRNA expression patterns and DNA methylation patterns more characteristic of differentiating than proliferating neural stem cells. This balance change may underlie neurodevelopmental disorders. (PMID:25966365)
• Based on segregation analysis of a patient (case 296491) with an intragenic deletion of the MBD5 gene, we classified deletions of exons 3 to 4 of the 5’ untranslated region (UTR) of this gene as probably benign. The deletion of exon 3 was shared with the father and paternal uncle, both unaffected (PMID:28295210)
• A novel frameshift mutation c.254_255delGA (p.Arg85Asnfs*6) in the MBD5 gene was identified in a family with intellectual disability and epilepsy. (PMID:28807762)
• MBD5-related intellectual disability in a Vietnamese child. (PMID:33427406)
• Long-read whole-genome sequencing identified a partial MBD5 deletion in an exome-negative patient with neurodevelopmental disorder. (PMID:33510365)
• Early-Onset Dementia Associated with a Heterozygous, Nonsense, and de novo Variant in the MBD5 Gene. (PMID:34459404)
• [Clinical phenotypes and genetic features of epilepsy children with MBD5 gene variants]. (PMID:35385942)
• Germline mosaicism in a family with MBD5 haploinsufficiency. (PMID:36396431)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mbd5	ENSDARG00000059581
mus_musculus	Mbd5	ENSMUSG00000036792
rattus_norvegicus	Mbd5	ENSRNOG00000027596
drosophila_melanogaster	sba	FBGN0016754

Paralogs (1): MBD6 (ENSG00000166987)

Protein

Protein identifiers

Methyl-CpG-binding domain protein 5 — Q9P267 (reviewed: Q9P267)

Alternative names: Methyl-CpG-binding protein MBD5

All UniProt accessions (8): Q9P267, A0A0D9SEP6, A0A0D9SF16, A0A0D9SG23, A0A1B0GUJ9, A0A1B0GW10, A0A2R8YDL9, H7C066

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at ‘Lys-120’ (H2AK119ub1). Important for stability of PR-DUB components and stimulating its ubiquitinase activity. As part of the PR-DUB complex, associates with chromatin enriched in histone marks H3K4me1, H3K4me3, and H3K27Ac, but not in H3K27me3. The PR-DUB complex is an epigenetic regulator of gene expression, including genes involved in cell growth and survivability. MBD5 and MBD6 containing complexes associate with distinct chromatin regions enriched in genes involved in different pathways. Heterochromatin recruitment is not mediated by DNA methylation. The PR-DUB complex is an epigenetic regulator of gene expression, including genes involved in development, cell communication, signaling, cell proliferation and cell viability.

Subunit / interactions. Core component of the polycomb repressive deubiquitinase (PR-DUB) complex, at least composed of BAP1, one of ASXL1, ASXL2 or (probably) ASXL3, and one of MBD5 or MBD6. Distinct combinations of ASXL and MBD proteins may preferentially bind specific histone modification marks. The PR-DUB core associates with a number of accessory proteins, including FOXK1, FOXK2, KDM1B, HCFC1 and OGT; KDM1B specifically associates with ASXL2 PR-DUB complexes. Interacts (via MBD domain) with ASXL1, ASXL2 and ASXL3 (via PHD domain); the interaction is probably direct, mediates association with other PR-DUB complex core components.

Subcellular location. Nucleus. Chromosome Nucleus.

Tissue specificity. Detected in heart, placenta, liver, skeletal muscle, kidney and pancreas.

Disease relevance. Intellectual developmental disorder, autosomal dominant 1 (MRD1) [MIM:156200] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Possesses a methyl-binding domain (MBD) and a Pro-Trp-Trp-Pro (PWWP) domain. Both MBD and PWWP domains are necessary for chromocentric localization. Possesses a methyl-binding domain (MBD) but lacks the Pro-Trp-Trp-Pro (PWWP) domain. The MBD may lack methyl-binding activity.

Miscellaneous. Named ‘methyl-CpG-binding domain protein’ for homology to other methyl-CpG-binding domain proteins and the presence of an MBD domain, MBD5 and MBD6 may have evolutionarily lost the ability to bind methylated DNA and are recruited to heterochromatin by alternative signals.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P267-1	1	yes
Q9P267-2	2

RefSeq proteins (2): NP_001365049, NP_060798 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000313	PWWP_dom	Domain
IPR001739	Methyl_CpG_DNA-bd	Domain
IPR016177	DNA-bd_dom_sf	Homologous_superfamily

UniProt features (32 total): region of interest 10, compositionally biased region 7, sequence variant 7, domain 2, splice variant 2, mutagenesis site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P267-F1	43.20	0.02

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
39	disrupts association with heterochromatin containing chromocentres.
1399–1400	disrupts association with heterochromatin containing chromocentres.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5689603	UCH proteinases
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 366 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_BEHAVIOR, MODULE_255, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, MODULE_317, TGACCTY_ERR1_Q2, KAUFFMANN_DNA_REPAIR_GENES, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, COUP_01, GOBP_REGULATION_OF_BEHAVIOR, GOBP_REGULATION_OF_MULTICELLULAR_ORGANISM_GROWTH, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_GROWTH_HORMONE, TGCTGAY_UNKNOWN

GO Biological Process (6): nervous system development (GO:0007399), regulation of multicellular organism growth (GO:0040014), glucose homeostasis (GO:0042593), regulation of behavior (GO:0050795), positive regulation of growth hormone receptor signaling pathway (GO:0060399), regulation of multicellular organismal process (GO:0051239)

GO Molecular Function (3): chromatin binding (GO:0003682), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), chromocenter (GO:0010369), midbody (GO:0030496), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Deubiquitination	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of multicellular organismal process	2
binding	2
cellular anatomical structure	2
intracellular membraneless organelle	2
system development	1
multicellular organism growth	1
regulation of developmental growth	1
carbohydrate homeostasis	1
behavior	1
positive regulation of signal transduction	1
growth hormone receptor signaling pathway	1
regulation of growth hormone receptor signaling pathway	1
multicellular organismal process	1
regulation of biological process	1
nucleic acid binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
extracellular vesicle	1

Protein interactions and networks

STRING

1487 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MBD5	FOXK1	P85037	634
MBD5	Q08EI0	Q08EI0	633
MBD5	OGT	O15294	582
MBD5	MBD6	Q96DN6	575
MBD5	EHMT1	Q9H9B1	547
MBD5	LYPD6B	Q8NI32	541
MBD5	ASXL1	Q8IXJ9	528
MBD5	MBD4	O95243	525
MBD5	EPC2	Q52LR7	517
MBD5	CDKL5	O76039	516
MBD5	CHD8	Q9HCK8	512
MBD5	MECP2	P51608	480
MBD5	ADSL	P30566	441
MBD5	GRIN2B	Q13224	440
MBD5	BAP1	Q92560	440

IntAct

22 interactions, top by confidence:

A	B	Type	Score
BAP1	OGT	psi-mi:“MI:0914”(association)	0.730
MBD5	CBX5	psi-mi:“MI:0915”(physical association)	0.400
MBD5	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
KIAA1549	MBD5	psi-mi:“MI:0915”(physical association)	0.370
MBD5	NME2P1	psi-mi:“MI:0914”(association)	0.350
ASXL2	CTRL	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
HRAS	IGHV1-45	psi-mi:“MI:0914”(association)	0.350
ASXL1	OGT	psi-mi:“MI:0914”(association)	0.350
	MBD5	psi-mi:“MI:0915”(physical association)	0.000
chi36	MBD5	psi-mi:“MI:0915”(physical association)	0.000
MBD5	ureC	psi-mi:“MI:0915”(physical association)	0.000
MBD5	acrA1	psi-mi:“MI:0915”(physical association)	0.000
fadL	MBD5	psi-mi:“MI:0915”(physical association)	0.000
MBD5	mdlB6	psi-mi:“MI:0915”(physical association)	0.000
Fla FV	MBD5	psi-mi:“MI:0915”(physical association)	0.000
MBD5	lipB	psi-mi:“MI:0915”(physical association)	0.000
MBD5	epd	psi-mi:“MI:0915”(physical association)	0.000
MBD5	APC	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (131): UBE2T (Affinity Capture-MS), EIF2S2 (Affinity Capture-MS), PMVK (Affinity Capture-MS), HDGFRP2 (Affinity Capture-MS), UBE2E1 (Affinity Capture-MS), NME2P1 (Affinity Capture-MS), NAA15 (Affinity Capture-MS), ETF1 (Affinity Capture-MS), SNX3 (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), RHOA (Affinity Capture-MS), UBA6 (Affinity Capture-MS), MBD5 (Affinity Capture-MS), MBD5 (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS)

ESM2 similar proteins: A0A096MJY4, A0A1L8H0H2, A1L2P5, A2ICN5, A2VDZ3, A4UTP7, B1AYB6, F8VPJ6, O54826, O94900, P19538, P22199, P23682, P55197, P91607, P91686, P91705, P91943, Q02078, Q03413, Q03414, Q06413, Q1KKS7, Q2KHR2, Q2KIA0, Q2MJT0, Q3LHL9, Q3V5Z9, Q5R444, Q5REW7, Q60929, Q66JW3, Q6P539, Q6YXY2, Q8BUR3, Q8CFN5, Q8VII8, Q8WU58, Q8WYQ9, Q91690

Diamond homologs: A8JR92, B1AYB6, O88508, Q1LZ53, Q3TY92, Q96DN6, Q9P267, Q9Y6K1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MBD5	up-regulates	Chromatine_condensation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1881 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	119
Likely pathogenic	45
Uncertain significance	938
Likely benign	537
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069933	NM_001378120.1(MBD5):c.469_476del (p.Thr157fs)	Pathogenic
1072505	NM_001378120.1(MBD5):c.4585C>T (p.Arg1529Ter)	Pathogenic
1074163	NM_001378120.1(MBD5):c.707C>G (p.Ser236Ter)	Pathogenic
1075127	NM_001378120.1(MBD5):c.180C>A (p.Cys60Ter)	Pathogenic
1075681	NM_001378120.1(MBD5):c.1449del (p.Ser484fs)	Pathogenic
1075828	NM_001378120.1(MBD5):c.598C>T (p.Arg200Ter)	Pathogenic
1292054	NM_001378120.1(MBD5):c.3828dup (p.Asn1277fs)	Pathogenic
1298863	GRCh37/hg19 2q23.1(chr2:149216328-149260078)x1	Pathogenic
1328442	GRCh37/hg19 2q23.1(chr2:148726315-148824342)x1	Pathogenic
1340347	GRCh37/hg19 2q23.1(chr2:148762386-148932571)x1	Pathogenic
1413133	NM_001378120.1(MBD5):c.1188del (p.Met396fs)	Pathogenic
1423243	NM_001378120.1(MBD5):c.3907C>T (p.Gln1303Ter)	Pathogenic
1425995	NM_001378120.1(MBD5):c.143del (p.Glu48fs)	Pathogenic
1427792	NM_001378120.1(MBD5):c.2356C>T (p.Gln786Ter)	Pathogenic
1429634	NM_001378120.1(MBD5):c.3769del (p.Asp1257fs)	Pathogenic
1437405	NM_001378120.1(MBD5):c.1379C>A (p.Ser460Ter)	Pathogenic
1439480	NM_001378120.1(MBD5):c.1648del (p.Ser550fs)	Pathogenic
1450097	NM_001378120.1(MBD5):c.2113del (p.Leu705fs)	Pathogenic
1451143	NM_001378120.1(MBD5):c.4729del (p.Ser1577fs)	Pathogenic
1453746	NM_001378120.1(MBD5):c.1499_1500dup (p.Arg501fs)	Pathogenic
1455491	NM_001378120.1(MBD5):c.3572del (p.Thr1190_Leu1191insTer)	Pathogenic
1456069	NM_001378120.1(MBD5):c.3790A>T (p.Arg1264Ter)	Pathogenic
1457775	NM_001378120.1(MBD5):c.710_725del (p.Ile237fs)	Pathogenic
1459105	NC_000002.11:g.(?149216328)(149228050_?)del	Pathogenic
1460283	NC_000002.11:g.(?148730288)(149270510_?)del	Pathogenic
1526910	GRCh37/hg19 2q22.3-23.1(chr2:148698523-148900148)	Pathogenic
1526911	GRCh37/hg19 2q23.1(chr2:148728326-148851964)	Pathogenic
1526912	GRCh37/hg19 2q23.1(chr2:148728409-149130479)	Pathogenic
1526913	GRCh37/hg19 2q23.1(chr2:148746282-149079105)	Pathogenic
1526914	GRCh37/hg19 2q23.1(chr2:148894900-148979973)	Pathogenic

SpliceAI

5790 predictions. Top by Δscore:

Variant	Effect	Δscore
2:148178696:TTA:T	acceptor_loss	1.0000
2:148178697:TA:T	acceptor_loss	1.0000
2:148178698:A:AC	acceptor_loss	1.0000
2:148178698:A:AG	acceptor_gain	1.0000
2:148178698:AGAT:A	acceptor_gain	1.0000
2:148178699:G:GC	acceptor_gain	1.0000
2:148178699:GA:G	acceptor_gain	1.0000
2:148178699:GAT:G	acceptor_gain	1.0000
2:148178699:GATG:G	acceptor_gain	1.0000
2:148178699:GATGT:G	acceptor_gain	1.0000
2:148178791:AAG:A	donor_gain	1.0000
2:148178792:AG:A	donor_gain	1.0000
2:148178792:AGG:A	donor_loss	1.0000
2:148178793:GG:G	donor_gain	1.0000
2:148178794:G:GA	donor_loss	1.0000
2:148178794:G:GG	donor_gain	1.0000
2:148233375:G:GT	donor_gain	1.0000
2:148393377:A:T	donor_gain	1.0000
2:148448856:A:G	donor_gain	1.0000
2:148463735:CCA:C	acceptor_loss	1.0000
2:148463738:GGT:G	acceptor_gain	1.0000
2:148463817:C:G	donor_gain	1.0000
2:148463871:G:GT	donor_gain	1.0000
2:148463916:ACAAG:A	donor_loss	1.0000
2:148463918:AAG:A	donor_loss	1.0000
2:148463919:AG:A	donor_loss	1.0000
2:148463920:G:GC	donor_loss	1.0000
2:148463920:G:GG	donor_gain	1.0000
2:148463921:TA:T	donor_loss	1.0000
2:148468335:C:G	acceptor_gain	1.0000

AlphaMissense

9945 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:148458831:T:A	W25R	1.000
2:148458831:T:C	W25R	1.000
2:148458832:G:C	W25S	1.000
2:148458833:G:C	W25C	1.000
2:148458833:G:T	W25C	1.000
2:148458837:C:A	R27S	1.000
2:148458864:T:G	Y36D	1.000
2:148462617:T:A	V50D	1.000
2:148462625:T:G	Y53D	1.000
2:148462629:T:C	L54P	1.000
2:148462646:T:A	C60S	1.000
2:148462646:T:C	C60R	1.000
2:148462647:G:A	C60Y	1.000
2:148462647:G:C	C60S	1.000
2:148462648:C:G	C60W	1.000
2:148462651:G:C	K61N	1.000
2:148462651:G:T	K61N	1.000
2:148462652:T:A	C62S	1.000
2:148462652:T:C	C62R	1.000
2:148462653:G:A	C62Y	1.000
2:148462653:G:C	C62S	1.000
2:148462654:T:G	C62W	1.000
2:148462664:T:A	C66S	1.000
2:148462664:T:C	C66R	1.000
2:148462665:G:C	C66S	1.000
2:148462666:T:G	C66W	1.000
2:148463742:T:C	F74L	1.000
2:148463743:T:C	F74S	1.000
2:148463744:T:A	F74L	1.000
2:148463744:T:G	F74L	1.000

dbSNP variants (sampled 300 via entrez): RS1000005945 (2:148216073 A>G), RS1000011580 (2:148125224 T>A), RS1000013508 (2:148072456 A>G), RS1000024227 (2:148397609 G>A), RS1000026582 (2:148387634 G>A), RS1000028185 (2:148127140 TG>T), RS1000033420 (2:148391770 T>C,G), RS1000041061 (2:148318350 T>G), RS1000063184 (2:148472140 C>G), RS1000078208 (2:148126704 A>G), RS1000080271 (2:148127411 A>G), RS1000086650 (2:148300742 G>A), RS1000086669 (2:148391443 G>C), RS1000088807 (2:148272767 A>G), RS1000103509 (2:148256739 A>C,G)

Disease associations

OMIM: gene MIM:611472 | disease phenotypes: MIM:156200, MIM:616346, MIM:181500, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 1	Strong	Autosomal dominant
complex neurodevelopmental disorder	Strong	Autosomal dominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (13): intellectual disability, autosomal dominant 1 (MONDO:0007974), autism spectrum disorder (MONDO:0005258), complex neurodevelopmental disorder (MONDO:0100038), microcephaly (MONDO:0001149), intellectual disability (MONDO:0001071), developmental and epileptic encephalopathy, 31A (MONDO:0014598), 2q23.1 microdeletion syndrome (MONDO:0016459), schizophrenia (MONDO:0005090), autism (MONDO:0005260), neurodevelopmental disorder (MONDO:0700092), intellectual disability, autosomal dominant (MONDO:0100172), cleft palate (MONDO:0016064), autosomal dominant non-syndromic intellectual disability (MONDO:0015802)

Orphanet (7): 2q23.1 microdeletion syndrome (Orphanet:228402), Non-specific syndromic intellectual disability (Orphanet:528084), Lennox-Gastaut syndrome (Orphanet:2382), Cleft palate (Orphanet:2014), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

96 total (30 of 96 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000331	Short chin
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000448	Prominent nose
HP:0000457	Depressed nasal ridge
HP:0000483	Astigmatism
HP:0000505	Visual impairment
HP:0000527	Long eyelashes
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000565	Esotropia

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST005171_30	QT interval	1.000000e-06
GCST006061_227	Atrial fibrillation	2.000000e-08
GCST006923_4	Loneliness	2.000000e-08
GCST006924_15	Loneliness (MTAG)	2.000000e-08
GCST007272_20	Pulse pressure	3.000000e-58
GCST008971_93	Urate levels	7.000000e-09
GCST009255_13	Fourth ventricle volume	7.000000e-06
GCST010002_399	Refractive error	2.000000e-10
GCST012110_1	Loneliness	5.000000e-07
GCST012114_2	Sociability score	3.000000e-08
GCST90002382_79	Eosinophil percentage of white cells	2.000000e-09
GCST90002393_384	Monocyte count	2.000000e-18
GCST90002394_12	Monocyte percentage of white cells	4.000000e-13

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0007865	loneliness measurement
EFO:0005763	pulse pressure measurement
EFO:0004531	urate measurement
EFO:0009592	social interaction measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
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
C566947	Mental Retardation, Autosomal Dominant 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation	7
trichostatin A	affects cotreatment, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Benzo(a)pyrene	decreases expression, affects expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bufotalin	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
N-isopropyl-N-phenyl-4-phenylenediamine	affects response to substance	1
sodium arsenite	increases abundance, increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression, affects cotreatment	1
Decitabine	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_5T12	GM23711	Transformed cell line	Female
CVCL_AZ37	GM24585	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder