TBR1

Summary

TBR1 (T-box brain transcription factor 1, HGNC:11590) is a protein-coding gene on chromosome 2q24.2, encoding T-box brain protein 1 (Q16650). Transcriptional repressor involved in multiple aspects of cortical development, including neuronal migration, laminar and areal identity, and axonal projection. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of a conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase.

Source: NCBI Gene 10716 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 313 total — 25 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 40
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006593

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11590
Approved symbol	TBR1
Name	T-box brain transcription factor 1
Location	2q24.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000136535
Ensembl biotype	protein_coding
OMIM	604616
Entrez	10716

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000389554, ENST00000410035, ENST00000411412, ENST00000463544, ENST00000477804, ENST00000489530

RefSeq mRNA: 1 — MANE Select: NM_006593 NM_006593

CCDS: CCDS33310

Canonical transcript exons

ENST00000389554 — 6 exons

Exon	Start	End
ENSE00001506191	161423369	161425870
ENSE00001506193	161418892	161419050
ENSE00001506195	161417676	161417830
ENSE00001506196	161416297	161417102
ENSE00003491155	161420196	161420257
ENSE00003518816	161418201	161418322

Expression profiles

Bgee: expression breadth broad, 58 present calls, max score 99.13.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.6501 / max 720.9173, expressed in 104 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23322	2.5815	84
23323	1.0725	69
23321	0.4839	65
23331	0.2711	54
23330	0.2192	54
23332	0.2028	52
23327	0.1601	45
23324	0.1022	40
23329	0.0939	40
23328	0.0852	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.13	gold quality
ganglionic eminence	UBERON:0004023	96.80	gold quality
Brodmann (1909) area 10	UBERON:0013541	94.81	gold quality
frontal pole	UBERON:0002795	94.45	gold quality
prefrontal cortex	UBERON:0000451	89.58	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.60	gold quality
frontal cortex	UBERON:0001870	85.30	gold quality
right frontal lobe	UBERON:0002810	85.07	gold quality
cingulate cortex	UBERON:0003027	84.74	gold quality
anterior cingulate cortex	UBERON:0009835	84.74	gold quality
neocortex	UBERON:0001950	84.71	gold quality
cerebral cortex	UBERON:0000956	80.66	gold quality
postcentral gyrus	UBERON:0002581	80.27	silver quality
embryo	UBERON:0000922	78.43	gold quality
superior frontal gyrus	UBERON:0002661	76.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.68	gold quality
parietal lobe	UBERON:0001872	75.42	silver quality
ventricular zone	UBERON:0003053	75.11	gold quality
amygdala	UBERON:0001876	72.50	gold quality
Brodmann (1909) area 46	UBERON:0006483	70.80	silver quality
primary visual cortex	UBERON:0002436	68.94	gold quality
temporal lobe	UBERON:0001871	68.21	gold quality
telencephalon	UBERON:0001893	67.99	gold quality
Ammon’s horn	UBERON:0001954	67.30	gold quality
occipital lobe	UBERON:0002021	64.52	gold quality
forebrain	UBERON:0001890	63.45	gold quality
entorhinal cortex	UBERON:0002728	63.44	silver quality
middle frontal gyrus	UBERON:0002702	62.16	gold quality
paraflocculus	UBERON:0005351	61.78	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	411.77
E-GEOD-75140	yes	352.91
E-HCAD-5	yes	62.65
E-ANND-3	no	3.60

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
AUTS2	Activation
CS
EOMES
FEZF2	Repression
GRIN2B
RELN	Unknown
TBR1

JASPAR motifs

Motif	Name	Family
MA0802.1	TBR1	TBrain-related factors
MA0802.2	TBR1	TBrain-related factors

JASPAR matrix evidence (PMIDs): PMID:12093383

Upstream regulators (CollecTRI, top): FEZF2, TBR1

miRNA regulators (miRDB)

155 targeting TBR1, 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-513A-5P	100.00	69.77	2465
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
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-3162-3P	100.00	65.37	363
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-568	99.98	69.86	2084
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

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 9)

• AUTS1/AUTS5 linkage to immp2l-dock4 gene region may be involved in autism susceptibilty (PMID:19401682)
• TBR1 homodimerizes; it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and this interaction is disrupted by pathogenic mutations affecting either protein (PMID:25232744)
• We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of utism spectrum disorders cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious (PMID:30250039)
• our study supports the observation that TBR1-related disorders range from intellectual disability to frontal pachygyria. We also highlight the need for first-line, good quality neuroimaging for patients with intellectual disability. (PMID:30268909)
• De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature. (PMID:32005960)
• Age-, tumor-, and metastatic tissue-associated DNA hypermethylation of a T-box brain 1 locus in human kidney tissue. (PMID:32070431)
• [Identification of a novel TBR1 gene variant in a Chinese pedigree affected with intellectual developmental disorder with autism and speech delay]. (PMID:34625926)
• Shared and Distinct Functional Effects of Patient-Specific Tbr1 Mutations on Cortical Development. (PMID:35944998)
• Characterization of the TBR1 interactome: variants associated with neurodevelopmental disorders disrupt novel protein interactions. (PMID:36579832)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbr1b	ENSDARG00000004712
mus_musculus	Tbr1	ENSMUSG00000035033
rattus_norvegicus	Tbr1	ENSRNOG00000005049
drosophila_melanogaster	H15	FBGN0016660
drosophila_melanogaster	mid	FBGN0261963
drosophila_melanogaster	ocm	FBGN0266083
caenorhabditis_elegans		WBGENE00003106
caenorhabditis_elegans		WBGENE00004750
caenorhabditis_elegans		WBGENE00006545
caenorhabditis_elegans		WBGENE00006546
caenorhabditis_elegans		WBGENE00006556
caenorhabditis_elegans		WBGENE00006557
caenorhabditis_elegans		WBGENE00006559
caenorhabditis_elegans		WBGENE00044798

Paralogs (16): TBX21 (ENSG00000073861), TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX18 (ENSG00000112837), TBX2 (ENSG00000121068), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBX19 (ENSG00000143178), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box brain protein 1 — Q16650 (reviewed: Q16650)

Alternative names: TES-56

All UniProt accessions (2): Q16650, H7C0B1

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor involved in multiple aspects of cortical development, including neuronal migration, laminar and areal identity, and axonal projection. As transcriptional repressor of FEZF2, it blocks the formation of the corticospinal (CS) tract from layer 6 projection neurons, thereby restricting the origin of CS axons specifically to layer 5 neurons.

Subunit / interactions. Homodimer. Part of a complex containing CASK, TBR1 and TSPYL2; may modulate gene expression in response to neuronal synaptic activity. Interacts with FOXP2. Interacts with FOXP1. Interacts with BCL11A.

Subcellular location. Nucleus.

Tissue specificity. Brain.

Disease relevance. Intellectual developmental disorder with autism and speech delay (IDDAS) [MIM:606053] An autosomal dominant neurodevelopmental disorder characterized by varying degrees of intellectual disability, autism spectrum disorder, and language deficits. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16650-1	1	yes
Q16650-2	2

RefSeq proteins (1): NP_006584* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR032385	T-box_assoc	Domain
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907, PF16176

UniProt features (28 total): sequence variant 10, modified residue 4, region of interest 4, compositionally biased region 4, mutagenesis site 2, chain 1, DNA-binding region 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16650-F1	56.17	0.25

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 (4): 408, 410, 594, 641

Mutagenesis-validated functional residues (2):

Position	Phenotype
394–682	decreased interaction with bcl11a.
568–682	no effect on interaction with bcl11a.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 322 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, YAGI_AML_WITH_INV_16_TRANSLOCATION, NKX25_02, LFA1_Q6, GOBP_ASSOCIATIVE_LEARNING, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_AXON_GUIDANCE, HNF1_Q6, LHX3_01, CAGCTG_AP4_Q5, GOBP_FOREBRAIN_DEVELOPMENT, CEBPB_01

GO Biological Process (19): conditioned taste aversion (GO:0001661), cell fate specification (GO:0001708), chromatin remodeling (GO:0006338), regulation of transcription by RNA polymerase II (GO:0006357), brain development (GO:0007420), specification of animal organ identity (GO:0010092), gene expression (GO:0010467), regulation of neuron projection development (GO:0010975), amygdala development (GO:0021764), commitment of neuronal cell to specific neuron type in forebrain (GO:0021902), cerebral cortex development (GO:0021987), hindbrain development (GO:0030902), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of axon guidance (GO:1902667), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), neuron differentiation (GO:0030182), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (7): 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 transcription factor activity (GO:0003700), protein kinase binding (GO:0019901), chromatin DNA binding (GO:0031490), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
anatomical structure development	3
DNA-templated transcription	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
feeding behavior	1
associative learning	1
cell fate commitment	1
cellular developmental process	1
chromatin organization	1
central nervous system development	1
animal organ development	1
head development	1
regionalization	1
animal organ formation	1
macromolecule biosynthetic process	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
limbic system development	1
forebrain neuron fate commitment	1
pallium development	1
brain development	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
axon guidance	1
regulation of neuron projection development	1
regulation of chemotaxis	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cell differentiation	1
generation of neurons	1
positive regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1

Protein interactions and networks

STRING

2172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBR1	FEZF2	Q8TBJ5	932
TBR1	PAX6	P26367	907
TBR1	SATB2	Q9UPW6	891
TBR1	BCL11B	Q9C0K0	883
TBR1	CUX1	P39880	849
TBR1	CASK	O14936	817
TBR1	FOXG1	P55315	810
TBR1	EMX1	Q04741	804
TBR1	RELN	P78509	804
TBR1	FOXP2	O15409	801
TBR1	NEUROD6	Q96NK8	773
TBR1	CALB2	P22676	765
TBR1	NES	P48681	745
TBR1	GFAP	P14136	730
TBR1	LHX6	Q9UPM6	718

IntAct

77 interactions, top by confidence:

A	B	Type	Score
ATXN1	TBR1	psi-mi:“MI:0915”(physical association)	0.660
TBR1	APP	psi-mi:“MI:0915”(physical association)	0.560
TBR1		psi-mi:“MI:0915”(physical association)	0.560
PRKN	TBR1	psi-mi:“MI:0915”(physical association)	0.560
APP	TBR1	psi-mi:“MI:0915”(physical association)	0.560
SNCA	TBR1	psi-mi:“MI:0915”(physical association)	0.560
HTT	TBR1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (189): CASK (Two-hybrid), RMND5B (Affinity Capture-MS), TBR1 (Affinity Capture-MS), TSPYL2 (Affinity Capture-Western), CASK (Affinity Capture-Western), TBR1 (Affinity Capture-MS), TBR1 (Affinity Capture-MS), TBR1 (Affinity Capture-MS), TBR1 (Affinity Capture-MS), TBR1 (Affinity Capture-MS), TBR1 (Affinity Capture-MS), TBR1 (Affinity Capture-Western), TBR1 (Affinity Capture-Western), TBR1 (Proximity Label-MS), TBR1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8V0YY16, A1YEY5, A1YG57, A2T733, A2T7P4, A4L7N3, A8MTJ6, B5RHS5, E1BPQ1, E9PZZ1, F6W2R2, G3V7R4, O35137, O54839, O70306, O95935, O95936, P09084, P31260, P31277, P31310, P31314, P43345, P56915, P57082, P70325, P79944, Q02591, Q05826, Q12778, Q12948, Q15784, Q16650, Q4LAL6, Q5VZB9, Q61572, Q62414, Q63689, Q64336, Q810W5

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TBR1	“up-regulates activity”	FOXP2	binding
TBR1	“up-regulates quantity by expression”	AUTS2	“transcriptional regulation”
CASK	up-regulates	TBR1	binding
TBR1	“down-regulates quantity by repression”	FEZF2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	36
Uncertain significance	190
Likely benign	41
Benign	4

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1164049	NM_006593.4(TBR1):c.1132A>T (p.Thr378Ser)	Pathogenic
1308658	NM_006593.4(TBR1):c.969+1G>C	Pathogenic
1343070	NM_006593.4(TBR1):c.196_199del (p.Asp66fs)	Pathogenic
1698967	NM_006593.4(TBR1):c.381del (p.Gly128fs)	Pathogenic
1723006	NM_006593.4(TBR1):c.1362del (p.Pro455fs)	Pathogenic
1804068	NM_006593.4(TBR1):c.1250C>A (p.Ser417Ter)	Pathogenic
1895456	NM_006593.4(TBR1):c.1126G>C (p.Asp376His)	Pathogenic
2283476	NM_006593.4(TBR1):c.165del (p.Thr56fs)	Pathogenic
2573063	NM_006593.4(TBR1):c.412_413dup (p.Ile139fs)	Pathogenic
3065986	NM_006593.4(TBR1):c.1190+2T>G	Pathogenic
3242447	NM_006593.4(TBR1):c.163dup (p.Ile55fs)	Pathogenic
3254867	NM_006593.4(TBR1):c.1220dup (p.Thr408fs)	Pathogenic
3340870	NM_006593.4(TBR1):c.1648_1657dup (p.Tyr553fs)	Pathogenic
3342333	NM_006593.4(TBR1):c.1128+2T>C	Pathogenic
3389597	NM_006593.4(TBR1):c.967C>T (p.Gln323Ter)	Pathogenic
3777734	NM_006593.4(TBR1):c.507C>A (p.Tyr169Ter)	Pathogenic
4075947	GRCh37/hg19 2q24.2(chr2:162274065-162302268)x1	Pathogenic
520662	NM_006593.4(TBR1):c.667G>C (p.Glu223Gln)	Pathogenic
599048	NM_006593.4(TBR1):c.405del (p.Ala136fs)	Pathogenic
599049	NM_006593.4(TBR1):c.1049dup (p.Thr350_Ser351insTer)	Pathogenic
599050	NM_006593.4(TBR1):c.682A>G (p.Lys228Glu)	Pathogenic
599051	NM_006593.4(TBR1):c.1120A>C (p.Asn374His)	Pathogenic
599052	NM_006593.4(TBR1):c.813G>T (p.Trp271Cys)	Pathogenic
599053	NM_006593.4(TBR1):c.1165A>G (p.Lys389Glu)	Pathogenic
807510	NM_006593.4(TBR1):c.1731dup (p.Ala578fs)	Pathogenic
1299335	NM_006593.4:c.(1128+1_1129-1)_(1190+1_1191-1)del	Likely pathogenic
1342892	NM_006593.4(TBR1):c.1162G>C (p.Ala388Pro)	Likely pathogenic
1710258	NM_006593.4(TBR1):c.1206T>A (p.Cys402Ter)	Likely pathogenic
1758318	NM_006593.4(TBR1):c.732_734delinsGGTCTGGTTTTAACATT (p.Asp245delinsValTrpPheTer)	Likely pathogenic
2325692	NM_006593.4(TBR1):c.638T>A (p.Leu213His)	Likely pathogenic

SpliceAI

618 predictions. Top by Δscore:

Variant	Effect	Δscore
2:161417099:G:T	donor_gain	1.0000
2:161418195:CTCTA:C	acceptor_loss	1.0000
2:161418196:TCTA:T	acceptor_loss	1.0000
2:161418197:CTA:C	acceptor_loss	1.0000
2:161418198:TAG:T	acceptor_loss	1.0000
2:161418199:A:AG	acceptor_gain	1.0000
2:161418199:AG:A	acceptor_gain	1.0000
2:161418199:AGG:A	acceptor_loss	1.0000
2:161418200:G:GT	acceptor_gain	1.0000
2:161418200:GG:G	acceptor_gain	1.0000
2:161418200:GGA:G	acceptor_gain	1.0000
2:161418200:GGAA:G	acceptor_gain	1.0000
2:161418320:CAG:C	donor_loss	1.0000
2:161418321:AGG:A	donor_loss	1.0000
2:161418322:GGT:G	donor_loss	1.0000
2:161418323:G:A	donor_loss	1.0000
2:161418324:T:G	donor_loss	1.0000
2:161419046:CGGAT:C	donor_gain	1.0000
2:161419047:GGAT:G	donor_gain	1.0000
2:161419047:GGATG:G	donor_gain	1.0000
2:161419048:G:GT	donor_gain	1.0000
2:161419048:G:T	donor_gain	1.0000
2:161419048:GAT:G	donor_gain	1.0000
2:161419049:AT:A	donor_gain	1.0000
2:161419049:ATGT:A	donor_loss	1.0000
2:161419050:TGTA:T	donor_loss	1.0000
2:161419051:G:GG	donor_gain	1.0000
2:161419051:GT:G	donor_loss	1.0000
2:161419052:T:G	donor_loss	1.0000
2:161420191:GCCA:G	acceptor_loss	1.0000

AlphaMissense

4466 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:161417033:T:A	L208Q	1.000
2:161417033:T:C	L208P	1.000
2:161417048:T:A	L213H	1.000
2:161417048:T:C	L213P	1.000
2:161417050:T:A	W214R	1.000
2:161417050:T:C	W214R	1.000
2:161417051:G:C	W214S	1.000
2:161417052:G:C	W214C	1.000
2:161417052:G:T	W214C	1.000
2:161417059:T:A	F217I	1.000
2:161417059:T:C	F217L	1.000
2:161417059:T:G	F217V	1.000
2:161417060:T:C	F217S	1.000
2:161417060:T:G	F217C	1.000
2:161417061:T:A	F217L	1.000
2:161417061:T:G	F217L	1.000
2:161417075:C:A	T222K	1.000
2:161417075:C:G	T222R	1.000
2:161417077:G:A	E223K	1.000
2:161417078:A:C	E223A	1.000
2:161417078:A:G	E223G	1.000
2:161417078:A:T	E223V	1.000
2:161417079:G:C	E223D	1.000
2:161417079:G:T	E223D	1.000
2:161417081:T:A	M224K	1.000
2:161417081:T:C	M224T	1.000
2:161417081:T:G	M224R	1.000
2:161417082:G:A	M224I	1.000
2:161417082:G:C	M224I	1.000
2:161417082:G:T	M224I	1.000

dbSNP variants (sampled 300 via entrez): RS1000035819 (2:161419106 C>T), RS1000405813 (2:161423797 C>G), RS1000709178 (2:161415683 G>A,T), RS1000792087 (2:161422780 G>C), RS1001471027 (2:161422602 G>A), RS1001589776 (2:161415290 C>A), RS1001843943 (2:161421193 G>A), RS1001863790 (2:161419519 T>C), RS1002060102 (2:161415022 C>T), RS1002310663 (2:161421361 T>C), RS1002377428 (2:161420865 G>A), RS1002458172 (2:161421017 G>A), RS1002714164 (2:161419326 G>A), RS1003035023 (2:161425501 T>C), RS1003514869 (2:161419680 G>A)

Disease associations

OMIM: gene MIM:604616 | disease phenotypes: MIM:606053

GenCC curated gene-disease

Disease	Classification	Inheritance
autism	Definitive	Autosomal dominant
intellectual developmental disorder with autism and speech delay	Strong	Autosomal dominant
occipital pachygyria and polymicrogyria	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (7): neurodevelopmental disorder (MONDO:0700092), intellectual developmental disorder with autism and speech delay (MONDO:0011627), intellectual disability (MONDO:0001071), cerebral cortical dysplasia (MONDO:0017094), attention deficit-hyperactivity disorder (MONDO:0007743), occipital pachygyria and polymicrogyria (MONDO:0013583), autism (MONDO:0005260)

Orphanet (2): Cerebral cortical dysplasia (Orphanet:268950), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000175	Cleft palate
HP:0000190	Abnormal oral frenulum morphology
HP:0000274	Small face
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000358	Posteriorly rotated ears
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000525	Abnormality iris morphology
HP:0000568	Microphthalmia
HP:0000589	Coloboma
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0001188	Hand clenching
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001302	Pachygyria
HP:0001319	Neonatal hypotonia
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001518	Small for gestational age
HP:0001770	Toe syndactyly

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002598_20	Educational attainment	2.000000e-07
GCST003469_8	Response to cognitive-behavioural therapy in anxiety disorder	8.000000e-06
GCST005316_161	Intelligence (MTAG)	5.000000e-08
GCST007277_3	Tourette syndrome	2.000000e-07
GCST007327_127	Smoking status (ever vs never smokers)	3.000000e-09
GCST010698_7	Subcortical volume (min-P)	5.000000e-08
GCST010699_92	Brain morphology (min-P)	7.000000e-13
GCST010700_32	Cortical thickness (MOSTest)	1.000000e-08
GCST010701_4	Cortical surface area (MOSTest)	1.000000e-08
GCST010702_173	Subcortical volume (MOSTest)	5.000000e-16
GCST010703_19	Brain morphology (MOSTest)	1.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0007820	cognitive behavioural therapy
EFO:0004337	intelligence
EFO:0004318	smoking behavior
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D054220	Malformations of Cortical Development	C10.500.507; C16.131.666.507
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects methylation	1
potassium chromate(VI)	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
pentanal	increases expression	1
licochalcone B	increases expression	1
bisphenol S	increases methylation	1
Acetaminophen	increases expression	1
Arsenic	increases methylation	1
Benzo(a)pyrene	affects methylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Serpentine	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With 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
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation