GTF2IRD1

Summary

GTF2IRD1 (GTF2I repeat domain containing 1, HGNC:4661) is a protein-coding gene on chromosome 7q11.23, encoding General transcription factor II-I repeat domain-containing protein 1 (Q9UHL9). May be a transcription regulator involved in cell-cycle progression and skeletal muscle differentiation.

The protein encoded by this gene contains five GTF2I-like repeats and each repeat possesses a potential helix-loop-helix (HLH) motif. It may have the ability to interact with other HLH-proteins and function as a transcription factor or as a positive transcriptional regulator under the control of Retinoblastoma protein. This gene plays a role in craniofacial and cognitive development and mutations have been associated with Williams-Beuren syndrome, a multisystem developmental disorder caused by deletion of multiple genes at 7q11.23. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9569 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 232 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 186
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005685

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4661
Approved symbol	GTF2IRD1
Name	GTF2I repeat domain containing 1
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	MusTRD1, RBAP2, GTF3, WBSCR12, BEN, Cream1
Ensembl gene	ENSG00000006704
Ensembl biotype	protein_coding
OMIM	604318
Entrez	9569

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 38 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000265755, ENST00000424337, ENST00000455841, ENST00000470715, ENST00000476977, ENST00000486086, ENST00000489094, ENST00000909892, ENST00000909893, ENST00000909894, ENST00000909895, ENST00000909896, ENST00000909897, ENST00000909898, ENST00000909899, ENST00000909900, ENST00000909902, ENST00000909903, ENST00000929911, ENST00000929912, ENST00000929913, ENST00000929914, ENST00000929915, ENST00000929916, ENST00000929917, ENST00000929918, ENST00000929919, ENST00000971619, ENST00000971620, ENST00000971621, ENST00000971622, ENST00000971623, ENST00000971624, ENST00000971625, ENST00000971626, ENST00000971627, ENST00000971628, ENST00000971629, ENST00000971630, ENST00000971631

RefSeq mRNA: 4 — MANE Select: NM_005685 NM_001199207, NM_001410888, NM_005685, NM_016328

CCDS: CCDS47613, CCDS5571, CCDS56492, CCDS94121

Canonical transcript exons

ENST00000424337 — 27 exons

Exon	Start	End
ENSE00000404019	74590825	74591017
ENSE00000691312	74601044	74601180
ENSE00001039134	74559627	74559655
ENSE00001039136	74595014	74595051
ENSE00001147952	74589851	74589928
ENSE00001604832	74555438	74555494
ENSE00001804055	74453906	74454176
ENSE00001890344	74602365	74602605
ENSE00003512220	74518139	74518322
ENSE00003523203	74508075	74508203
ENSE00003542237	74519409	74519719
ENSE00003554404	74539879	74539968
ENSE00003562682	74558861	74559044
ENSE00003593057	74529734	74529917
ENSE00003603019	74547103	74547286
ENSE00003612701	74536167	74536275
ENSE00003631886	74557639	74557722
ENSE00003642504	74512830	74512971
ENSE00003651244	74544755	74544802
ENSE00003656037	74538136	74538173
ENSE00003656168	74524071	74524154
ENSE00003659544	74515441	74515596
ENSE00003676411	74555174	74555223
ENSE00003679089	74535113	74535138
ENSE00003683501	74538680	74538760
ENSE00003686150	74521208	74521297
ENSE00003694579	74545744	74545809

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 96.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.5130 / max 130.5176, expressed in 1646 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79089	6.7385	1553
79090	4.7259	1278
79088	3.7032	1362
79091	0.3137	198
79092	0.0317	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	96.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.74	gold quality
tibialis anterior	UBERON:0001385	95.45	gold quality
adenohypophysis	UBERON:0002196	94.75	gold quality
gastrocnemius	UBERON:0001388	94.57	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.20	gold quality
pituitary gland	UBERON:0000007	94.00	gold quality
muscle of leg	UBERON:0001383	93.60	gold quality
pharyngeal mucosa	UBERON:0000355	93.35	gold quality
biceps brachii	UBERON:0001507	93.31	gold quality
muscle organ	UBERON:0001630	93.15	gold quality
skeletal muscle organ	UBERON:0014892	93.15	gold quality
gluteal muscle	UBERON:0002000	93.07	gold quality
body of tongue	UBERON:0011876	92.88	gold quality
stromal cell of endometrium	CL:0002255	92.85	gold quality
skeletal muscle tissue	UBERON:0001134	92.68	gold quality
type B pancreatic cell	CL:0000169	92.24	silver quality
deltoid	UBERON:0001476	92.19	silver quality
triceps brachii	UBERON:0001509	91.49	gold quality
right lobe of thyroid gland	UBERON:0001119	91.40	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.40	gold quality
esophagus mucosa	UBERON:0002469	91.33	gold quality
quadriceps femoris	UBERON:0001377	91.17	gold quality
muscle tissue	UBERON:0002385	91.14	gold quality
mucosa of stomach	UBERON:0001199	90.87	gold quality
left lobe of thyroid gland	UBERON:0001120	90.76	gold quality
diaphragm	UBERON:0001103	90.72	silver quality
cortical plate	UBERON:0005343	90.62	gold quality
skin of leg	UBERON:0001511	90.58	gold quality
ectocervix	UBERON:0012249	90.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.74

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
ABCB1
CALCA
CISH
GTF2IRD1
LARGE1
RB1
SIRT7

Upstream regulators (CollecTRI, top): GTF2IRD1, MEF2C

miRNA regulators (miRDB)

25 targeting GTF2IRD1, 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-548C-3P	99.99	74.01	7587
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-6124	99.87	69.78	3551
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-4280	96.44	67.69	473
HSA-MIR-4474-5P	94.23	67.95	568

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 20)

• characterization and involvement in slow muscle-specific gene expression (PMID:12475981)
• role as a repressor of slow fiber-specific transcription through mechanisms involving direct interactions with MEF2C and the nuclear receptor co-repressor (PMID:12857748)
• GTF2IRD1 and GTF2I have roles in causing deficits on visual spatial functioning (PMID:12865760)
• human VEGFR-2 promoter is functionally counter-regulated by TFII-I and TFII-IRD1. (PMID:15941713)
• GTF2IRD1 is a genetic determinant of mammalian craniofacial and cognitive development (PMID:16293761)
• a regulator of slow fiber-specific genes (PMID:16494860)
• functional analysis of human GTF2IRD1 in regulation of three genes (HOXC8, GOOSECOID and TROPONIN I) (PMID:17346708)
• analysis of the consensus binding site for TFII-I family member BEN (PMID:18326499)
• GTF2IRD1 is associated with Williams syndrome facies and visual-spatial construction. (PMID:19205026)
• functional hemizygosity for the GTF2I and GTF2IRD1 genes is the main cause of the neurocognitive profile and some aspects of the gestalt phenotype of Williams-Beuren syndrome (PMID:19897463)
• Data show the existence of a negative autoregulatory mechanism that controls the level of GTF2IRD1 transcription via direct binding of the GTF2IRD1 protein to a highly conserved region of the GTF2IRD1 promoter containing an array of three binding sites. (PMID:20007321)
• This study provided evidences that insufficiency of GTF2IRD1 protein contributes to abnormalities of facial development, motor function and specific behavioural disorders that accompany Williams-Beuren syndrome. (PMID:22198572)
• CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome; GTF2IRD1 and GTF2I are the main genes causing the cognitive defects (PMID:22608712)
• GTF2IRD1 is SUMOylated by the SUMO E2 ligase UBC9 and the level of SUMOylation is enhanced by PIASxbeta. (PMID:23145142)
• GTF2IRD1 binding partners are mostly involved in chromatin modification and transcriptional regulation, whilst others indicate an unexpected role in connection with the primary cilium. (PMID:26275350)
• Study demonstrates a significant association between SLE in Chinese Han population and the GTF2I rs117026326 T allele/GTF2IRD1 rs4717901 C allele. (PMID:26320362)
• The mis-regulation of genes downstream of GTF2IRD1, including TbetaR2 and BMPR1b, also individually promoted mammary cancer development, and silencing of TbetaR2 suppressed GTF2IRD1-driven tumor promotion. (PMID:27239038)
• Among 110 SNPs within the 7q11.23 William’s Syndrome (WS) chromosomal region, we found one associated locus located at GTF2IRD1, which has been implicated in animal models of WS. (PMID:29884845)
• Study showed that GTF2IRD1 was overexpressed due to copy number amplification at Ch.7q in colorectal cancer (CRC). The expression of GTF2IRD1 was positively associated with the malignant pathological phenotype. Furthermore, high expression of GTF2IRD1 was an independent poor prognostic factor in CRC. Mechanistically, GTF2IRD1 promoted cell cycle progression by downregulation of TGFbetaR2 in CRC. (PMID:31758608)
• GTF2IRD1 overexpression promotes tumor progression and correlates with less CD8+ T cells infiltration in pancreatic cancer. (PMID:32936232)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gtf2ird1	ENSDARG00000022203
mus_musculus	Gtf2ird1	ENSMUSG00000023079
rattus_norvegicus	Gtf2ird1	ENSRNOG00000001478

Paralogs (18): ZMYM2 (ENSG00000121741), ZMYM5 (ENSG00000132950), THAP12 (ENSG00000137492), ZMYM4 (ENSG00000146463), ZMYM3 (ENSG00000147130), ZMYM6 (ENSG00000163867), KIAA1958 (ENSG00000165185), GTF2IRD2B (ENSG00000174428), EPM2AIP1 (ENSG00000178567), GTF2IRD2 (ENSG00000196275), ZMYM1 (ENSG00000197056), QRICH1 (ENSG00000198218), FAM200C (ENSG00000221886), FAM200A (ENSG00000221909), SCAND3 (ENSG00000232040), ZBED5 (ENSG00000236287), FAM200B (ENSG00000237765), GTF2I (ENSG00000263001)

Protein

Protein identifiers

General transcription factor II-I repeat domain-containing protein 1 — Q9UHL9 (reviewed: Q9UHL9)

Alternative names: General transcription factor III, MusTRD1/BEN, Muscle TFII-I repeat domain-containing protein 1, Slow-muscle-fiber enhancer-binding protein, USE B1-binding protein, Williams-Beuren syndrome chromosomal region 11 protein, Williams-Beuren syndrome chromosomal region 12 protein

All UniProt accessions (3): Q9UHL9, E9PFE2, H7C4Q8

UniProt curated annotations — full annotation on UniProt →

Function. May be a transcription regulator involved in cell-cycle progression and skeletal muscle differentiation. May repress GTF2I transcriptional functions, by preventing its nuclear residency, or by inhibiting its transcriptional activation. May contribute to slow-twitch fiber type specificity during myogenesis and in regenerating muscles. Binds troponin I slow-muscle fiber enhancer (USE B1). Binds specifically and with high affinity to the EFG sequences derived from the early enhancer of HOXC8.

Subunit / interactions. Interacts with the retinoblastoma protein (RB1) via its C-terminus.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in adult skeletal muscle, heart, fibroblast, bone and fetal tissues. Expressed at lower levels in all other tissues tested.

Disease relevance. GTF2IRD1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of GTF2IRD1 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.

Domain organisation. The N-terminal half may have an activating activity.

Similarity. Belongs to the TFII-I family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UHL9-1	1	yes
Q9UHL9-2	2
Q9UHL9-3	3

RefSeq proteins (4): NP_001186136, NP_001397817, NP_005676, NP_057412 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004212	GTF2I	Repeat
IPR016659	TF_II-I	Family
IPR036647	GTF2I-like_rpt_sf	Homologous_superfamily

Pfam: PF02946

UniProt features (87 total): cross-link 33, helix 14, strand 9, turn 8, repeat 5, region of interest 5, modified residue 3, compositionally biased region 2, splice variant 2, sequence conflict 2, chain 1, short sequence motif 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2D99	SOLUTION NMR
2DN5	SOLUTION NMR
2DZQ	SOLUTION NMR
2DZR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHL9-F1	64.55	0.30

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 (36): 448, 27, 94, 184, 212, 225, 238, 271, 294, 308, 337, 436, 439, 443, 567, 579, 588, 622, 638, 684 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
898–959	cytoplasmic localization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 574 (showing top): PAX4_01, RORA1_01, GOBP_SKELETAL_MUSCLE_ADAPTATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, TGACCTY_ERR1_Q2, FOXD3_01, GOBP_MUSCLE_ADAPTATION, GOBP_REGULATION_OF_SKELETAL_MUSCLE_ADAPTATION, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_MUSCLE_SYSTEM_PROCESS, chr7q11, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_DENDRITIC_CELL, MARIADASON_REGULATED_BY_HISTONE_ACETYLATION_DN

GO Biological Process (4): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), transcription by RNA polymerase II (GO:0006366), transition between slow and fast fiber (GO:0014886)

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 transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
DNA-templated transcription	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regulation of skeletal muscle adaptation	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription cis-regulatory region binding	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

778 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GTF2IRD1	CLIP2	Q9UDT6	857
GTF2IRD1	FKBP6	O75344	836
GTF2IRD1	FKBP10	Q96AY3	834
GTF2IRD1	TBL2	Q9Y4P3	820
GTF2IRD1	BAZ1B	Q9UIG0	782
GTF2IRD1	LIMK1	P53667	747
GTF2IRD1	TRIM50	Q86XT4	744
GTF2IRD1	BCL7B	Q9BQE9	737
GTF2IRD1	NSUN5	Q96P11	729
GTF2IRD1	PRDM16	Q9HAZ2	715
GTF2IRD1	EIF4H	Q15056	706
GTF2IRD1	FZD9	O00144	702
GTF2IRD1	RFC2	P32846	684
GTF2IRD1	ELN	P15502	653
GTF2IRD1	STX1A	Q16623	646

IntAct

131 interactions, top by confidence:

A	B	Type	Score
ZMYM2	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.670
GTF2IRD1	ZMYM2	psi-mi:“MI:0915”(physical association)	0.670
GTF2IRD1	ZMYM2	psi-mi:“MI:0403”(colocalization)	0.670
GTF2IRD1	ZMYM2	psi-mi:“MI:2364”(proximity)	0.670
SPOPL	SPOP	psi-mi:“MI:0914”(association)	0.590
GORASP2	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.560
MRFAP1L1	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.560
ZNF382	IPO8	psi-mi:“MI:0914”(association)	0.530
ULK3	AIP	psi-mi:“MI:0914”(association)	0.530
IFNA13	IFNA14	psi-mi:“MI:0914”(association)	0.530
INTS12	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.510
MBD3L1	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.510
ATF7IP	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.510
DCAF6	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	Homez	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	Nap1l2	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	Setd6	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	Zmym3	psi-mi:“MI:0915”(physical association)	0.510
PKP1	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	DCAF6	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	INTS12	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	MBD3L1	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	ATF7IP	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (141): GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS)

ESM2 similar proteins: A0JPK3, A1YFX5, A2RQG7, A7KBS4, F4JUI3, G3X9G7, O49498, P03131, P04605, P04614, P05909, P0C1K0, P11332, P12453, P18098, P24109, P35965, P98182, Q09424, Q0VCB0, Q19203, Q2YDJ5, Q3UZB0, Q567C6, Q5BI31, Q5EXX3, Q5M948, Q62396, Q6AXY9, Q6PB60, Q6PI77, Q71HP2, Q74124, Q7JUR5, Q7Z142, Q7Z2Y5, Q80YD3, Q86UQ0, Q8C0P7, Q8C6P8

Diamond homologs: A4IFA3, A7MB80, B7ZQJ9, P78347, Q5U2Y1, Q6EKJ0, Q86UP8, Q99NI3, Q9ESZ8, Q9JI57, Q9UHL9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GTF2IRD1	down-regulates	GTF2I

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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
Constitutive Signaling by Aberrant PI3K in Cancer	5	12.9×	4e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	9.9×	7e-03
PIP3 activates AKT signaling	6	8.2×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	128
Likely benign	51
Benign	17

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1703677	GRCh37/hg19 7q11.23(chr7:72686958-74155067)	Pathogenic
208388	NM_005685.4(GTF2IRD1):c.973C>T (p.Arg325Cys)	Likely pathogenic

SpliceAI

4478 predictions. Top by Δscore:

Variant	Effect	Δscore
7:74508069:CCACA:C	acceptor_loss	1.0000
7:74508070:CACAG:C	acceptor_loss	1.0000
7:74508071:ACAG:A	acceptor_gain	1.0000
7:74508071:ACAGG:A	acceptor_loss	1.0000
7:74508072:CAGGC:C	acceptor_loss	1.0000
7:74508073:A:AG	acceptor_gain	1.0000
7:74508073:AG:A	acceptor_gain	1.0000
7:74508073:AGGC:A	acceptor_gain	1.0000
7:74508073:AGGCG:A	acceptor_loss	1.0000
7:74508074:G:GA	acceptor_gain	1.0000
7:74508074:GG:G	acceptor_gain	1.0000
7:74508074:GGCG:G	acceptor_gain	1.0000
7:74508200:CATG:C	donor_gain	1.0000
7:74508201:ATG:A	donor_gain	1.0000
7:74508202:TG:T	donor_gain	1.0000
7:74508203:GG:G	donor_gain	1.0000
7:74508204:G:GG	donor_gain	1.0000
7:74508205:T:G	donor_loss	1.0000
7:74512825:CACA:C	acceptor_loss	1.0000
7:74512827:CAG:C	acceptor_loss	1.0000
7:74512828:A:AC	acceptor_loss	1.0000
7:74512828:A:AG	acceptor_gain	1.0000
7:74512828:AGT:A	acceptor_gain	1.0000
7:74512829:G:A	acceptor_loss	1.0000
7:74512829:G:GG	acceptor_gain	1.0000
7:74512829:GT:G	acceptor_gain	1.0000
7:74512829:GTG:G	acceptor_gain	1.0000
7:74512969:GCC:G	donor_gain	1.0000
7:74512970:CC:C	donor_gain	1.0000
7:74512971:CGTG:C	donor_loss	1.0000

AlphaMissense

6158 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:74512866:T:C	C54R	1.000
7:74518283:T:A	I189N	1.000
7:74518310:T:C	F198S	1.000
7:74521273:T:C	F328L	1.000
7:74521275:C:A	F328L	1.000
7:74521275:C:G	F328L	1.000
7:74521283:T:A	V331D	1.000
7:74524076:T:A	W338R	1.000
7:74524076:T:C	W338R	1.000
7:74524078:G:C	W338C	1.000
7:74524078:G:T	W338C	1.000
7:74524107:T:A	I348N	1.000
7:74524111:C:A	N349K	1.000
7:74524111:C:G	N349K	1.000
7:74524116:T:A	L351H	1.000
7:74524116:T:C	L351P	1.000
7:74524118:C:G	R352G	1.000
7:74524118:C:T	R352W	1.000
7:74524119:G:A	R352Q	1.000
7:74524119:G:C	R352P	1.000
7:74524119:G:T	R352L	1.000
7:74524124:T:C	C354R	1.000
7:74524126:T:G	C354W	1.000
7:74524132:G:C	Q356H	1.000
7:74524132:G:T	Q356H	1.000
7:74524134:T:A	I357N	1.000
7:74524134:T:C	I357T	1.000
7:74524134:T:G	I357S	1.000
7:74524137:T:C	L358P	1.000
7:74524139:T:A	F359I	1.000

dbSNP variants (sampled 300 via entrez): RS1000012134 (7:74533727 A>G), RS1000089484 (7:74456554 G>A,C), RS1000167924 (7:74501057 G>A), RS1000189785 (7:74462680 C>A,T), RS1000296098 (7:74600717 C>A), RS1000357359 (7:74506119 C>G,T), RS1000394820 (7:74506388 G>A,T), RS1000420002 (7:74456810 A>G), RS1000424628 (7:74510945 A>G), RS1000494448 (7:74499717 G>A,T), RS1000623806 (7:74599430 G>A), RS1000646045 (7:74501270 G>A), RS1000665062 (7:74467248 C>G), RS1000738121 (7:74576332 G>A), RS1000782724 (7:74468433 G>A,T)

Disease associations

OMIM: gene MIM:604318 | disease phenotypes: MIM:609757

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (3): 7q11.23 microduplication syndrome (MONDO:0012342), childhood-onset schizophrenia (MONDO:0957430), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): 7q11.23 microduplication syndrome (Orphanet:96121), Childhood-onset schizophrenia (Orphanet:641496)

HPO phenotypes

186 total (30 of 186 shown, HPO-id order):

HPO	Term
HP:0000010	Recurrent urinary tract infections
HP:0000014	Abnormality of the bladder
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000025	Functional abnormality of male internal genitalia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000075	Renal duplication
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000093	Proteinuria
HP:0000121	Nephrocalcinosis
HP:0000125	Pelvic kidney
HP:0000147	Polycystic ovaries
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000179	Thick lower lip vermilion
HP:0000212	Gingival overgrowth
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002217_1	Sjögren’s syndrome	1.000000e-53
GCST002931_3	Aluminium levels	8.000000e-06
GCST003123_18	Severe influenza A (H1N1) infection	2.000000e-16
GCST003599_2	Systemic lupus erythematosus	6.000000e-08
GCST005232_93	Neuroticism	3.000000e-08
GCST005752_2	Systemic lupus erythematosus	3.000000e-14
GCST007709_28	General factor of neuroticism	2.000000e-08
GCST008771_3	Age at suicide	3.000000e-08
GCST010244_425	Triglyceride levels	1.000000e-09
GCST011389_14	Rheumatoid arthritis	1.000000e-20

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:1001488	influenza A (H1N1)
EFO:0007660	neuroticism measurement
EFO:0006882	suicide behaviour measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C565723	Williams-Beuren Region Duplication Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects cotreatment, decreases expression, affects expression	5
Benzo(a)pyrene	affects methylation, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	increases abundance, increases expression, decreases methylation, affects cotreatment, decreases expression	3
Cyclosporine	decreases methylation, increases expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
bisphenol A	decreases methylation	1
geraniol	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	increases expression	1
tanespimycin	affects cotreatment, decreases expression	1
K 7174	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
VER 155008	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice