IQSEC2

Summary

IQSEC2 (IQ motif and Sec7 domain ArfGEF 2, HGNC:29059) is a protein-coding gene on chromosome Xp11.22, encoding IQ motif and SEC7 domain-containing protein 2 (Q5JU85). Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a guanine nucleotide exchange factor for the ARF family of small GTP-binding proteins. The encoded protein is a component of the postsynaptic density at excitatory synapses, and may play a critical role in cytoskeletal and synaptic organization through the activation of selected ARF substrates including ARF1 and ARF6. Mutations in this gene have been implicated in nonsyndromic X-linked cognitive disability. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 23096 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 1,521 total — 159 pathogenic, 65 likely-pathogenic
• Phenotypes (HPO): 122
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001111125

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29059
Approved symbol	IQSEC2
Name	IQ motif and Sec7 domain ArfGEF 2
Location	Xp11.22
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0522, BRAG1, IQ-ArfGEF
Ensembl gene	ENSG00000124313
Ensembl biotype	protein_coding
OMIM	300522
Entrez	23096

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000375365, ENST00000462054, ENST00000485377, ENST00000498281, ENST00000638521, ENST00000638583, ENST00000638630, ENST00000638869, ENST00000639161, ENST00000639485, ENST00000639543, ENST00000639642, ENST00000639796, ENST00000640005, ENST00000640436, ENST00000640442, ENST00000640694, ENST00000642864, ENST00000674510, ENST00000674761, ENST00000675719, ENST00000675731, ENST00000706952

RefSeq mRNA: 4 — MANE Select: NM_001111125 NM_001111125, NM_001243197, NM_001410736, NM_015075

CCDS: CCDS35298, CCDS48130, CCDS87748, CCDS94612

Canonical transcript exons

ENST00000642864 — 15 exons

Exon	Start	End
ENSE00000978597	53255800	53256061
ENSE00000978598	53254530	53254931
ENSE00000978602	53246969	53247135
ENSE00000978603	53243332	53243471
ENSE00000978604	53241784	53241909
ENSE00000978605	53239195	53239294
ENSE00000978607	53236322	53236495
ENSE00000978608	53235783	53235832
ENSE00001248006	53238145	53238306
ENSE00001248058	53250279	53251174
ENSE00001524937	53291895	53291924
ENSE00001639013	53248721	53248882
ENSE00001707292	53232876	53235184
ENSE00001777647	53248114	53248236
ENSE00003814959	53320417	53321350

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 96.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.4110 / max 133.4331, expressed in 1633 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199328	5.2616	1523
199331	2.8524	820
199329	0.7571	525
199327	0.3524	148
199332	0.1875	85

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	96.42	gold quality
cerebellar hemisphere	UBERON:0002245	95.99	gold quality
cerebellar cortex	UBERON:0002129	95.86	gold quality
right frontal lobe	UBERON:0002810	95.15	gold quality
cerebellum	UBERON:0002037	93.58	gold quality
gastrocnemius	UBERON:0001388	93.18	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.80	gold quality
prefrontal cortex	UBERON:0000451	92.71	gold quality
cingulate cortex	UBERON:0003027	92.05	gold quality
anterior cingulate cortex	UBERON:0009835	91.88	gold quality
muscle of leg	UBERON:0001383	91.78	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.55	gold quality
nucleus accumbens	UBERON:0001882	91.48	gold quality
right uterine tube	UBERON:0001302	90.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.64	gold quality
caudate nucleus	UBERON:0001873	90.25	gold quality
right adrenal gland	UBERON:0001233	90.20	gold quality
frontal cortex	UBERON:0001870	89.82	gold quality
amygdala	UBERON:0001876	89.72	gold quality
putamen	UBERON:0001874	89.70	gold quality
right adrenal gland cortex	UBERON:0035827	89.62	gold quality
neocortex	UBERON:0001950	89.52	gold quality
left adrenal gland cortex	UBERON:0035825	89.46	gold quality
left adrenal gland	UBERON:0001234	89.35	gold quality
adrenal cortex	UBERON:0001235	88.53	gold quality
cerebral cortex	UBERON:0000956	88.09	gold quality
telencephalon	UBERON:0001893	88.09	gold quality
stromal cell of endometrium	CL:0002255	87.93	gold quality
type B pancreatic cell	CL:0000169	87.89	silver quality
muscle organ	UBERON:0001630	87.89	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

121 targeting IQSEC2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 27)

• Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder (PMID:20473311)
• Truncating mutations in IQSEC2 are responsible for syndromic severe intellectual disability in male patients. (PMID:23674175)
• data supports recently published data suggesting that IQSEC2 plays a more significant role in the development of X-linked intellectual disability with seizures than previously anticipated. (PMID:24306141)
• the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2, is reported. (PMID:26059843)
• A novel splicing variant in IQSEC2 co-segregates in a family with an X-linked form of intellectual disability. (PMID:26733290)
• both Arf6 activation through GluN2B-BRAG1 during early development and the transition from BRAG1- to BRAG2-dependent Arf6 signaling induced by the GluN2 subunit switch are critical for the development of mature glutamatergic synapses. (PMID:26884337)
• This study demonstrates a dual role of BRAG1 in synaptic function. (PMID:27009485)
• argue that it is clinically appropriate to test for IQSEC2 mutations in male and female patients with this symptom profile but without a known genetic mutation (PMID:27010919)
• In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 in a girl with infantile-onset seizures variant of Rett syndrome (RTT) (PMID:27062609)
• This study demonstrated that IQSEC2 pathogenic variants are an important cause of epilepsy in intellectually disabled individuals from both genders. It can frequently manifest as an early onset EE. (PMID:27665735)
• identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1 (PMID:28213671)
• A truncating variant in IQSEC2 identified as a cause of fatal epileptic encephalopathy in two sisters. The IQSEC2 variant was identified in both surviving affected sisters but in neither parent. (PMID:28295038)
• IQSEC2 mutation is associated with syndromic intellectual disability. (PMID:28815955)
• This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development (PMID:30206421)
• There is a growing number of female patients with de novo loss-of-function variants in IQSEC2 have a more severe phenotype than the heterozygous state would predict, particularly if IQSEC2 is thought to escape X-inactivation. (PMID:30328660)
• This article reviews neuronal IQSEC2 signaling with emphasis on those aspects likely to be involved in autism. [review] (PMID:31234416)
• Human and mouse data reaffirm IQSEC2 as another disease gene with an unexpected X-chromosome heterozygous female phenotype. Our Iqsec2 mouse model recapitulates the phenotypes observed in human patients despite the differences in the IQSEC2/Iqsec2 gene X-chromosome inactivation between the species. (PMID:31439632)
• Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy. (PMID:32564198)
• IQSEC2 disorder: A new disease entity or a Rett spectrum continuum? (PMID:33368194)
• Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden IQSEC2 Pathogenic Variant in a Child with Intellectual Disability. (PMID:34229322)
• Characterization of spontaneous seizures and EEG abnormalities in a mouse model of the human A350V IQSEC2 mutation and identification of a possible target for precision medicine based therapy. (PMID:35344748)
• IQSEC2-related encephalopathy in males due to missense variants in the pleckstrin homology domain. (PMID:35347702)
• Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder. (PMID:36012761)
• [Genotypes and phenotypes of IQSEC2 gene variants related epilepsy]. (PMID:36444437)
• Molecular Insights into IQSEC2 Disease. (PMID:36902414)
• Molecular modeling of ARF6 dysregulation caused by mutations in IQSEC2. (PMID:37078745)
• Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions. (PMID:37787765)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	iqsec2b	ENSDARG00000077709
danio_rerio	iqsec2a	ENSDARG00000102125
mus_musculus	Iqsec2	ENSMUSG00000041115
rattus_norvegicus	Iqsec2	ENSRNOG00000058975
drosophila_melanogaster	siz	FBGN0026179
drosophila_melanogaster	Sec71	FBGN0028538
drosophila_melanogaster	garz	FBGN0264560
caenorhabditis_elegans		WBGENE00007703
caenorhabditis_elegans		WBGENE00008685
caenorhabditis_elegans	agef-1	WBGENE00012386

Paralogs (15): CYTH3 (ENSG00000008256), PSD (ENSG00000059915), MON2 (ENSG00000061987), ARFGEF1 (ENSG00000066777), CYTH4 (ENSG00000100055), CYTH2 (ENSG00000105443), GBF1 (ENSG00000107862), CYTH1 (ENSG00000108669), IQSEC3 (ENSG00000120645), ARFGEF2 (ENSG00000124198), PSD4 (ENSG00000125637), IQSEC1 (ENSG00000144711), PSD2 (ENSG00000146005), PSD3 (ENSG00000156011), FBXO8 (ENSG00000164117)

Protein

Protein identifiers

IQ motif and SEC7 domain-containing protein 2 — Q5JU85 (reviewed: Q5JU85)

All UniProt accessions (15): A0A1W2PPD3, A0A1W2PPE7, A0A1W2PPR2, A0A1W2PPU7, A0A1W2PQ34, A0A1W2PQP8, A0A1W2PQS2, A0A1W2PR10, Q5JU85, A0A1W2PR18, A0A1W2PR28, A0A1W2PRJ5, A0A6Q8PFR7, A0A6Q8PG99, A0A9L9PY69

UniProt curated annotations — full annotation on UniProt →

Function. Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in brain, kidney and small intestine. Weakly expressed in placenta, pancreas, ovary, prostate and liver.

Disease relevance. Intellectual developmental disorder, X-linked 1 (XLID1) [MIM:309530] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic forms present with associated physical, neurological and/or psychiatric manifestations. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the BRAG family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5JU85-2	1	yes
Q5JU85-3	2
Q5JU85-4	3

RefSeq proteins (4): NP_001104595, NP_001230126, NP_001397665, NP_055890 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000904	Sec7_dom	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR023394	Sec7_C_sf	Homologous_superfamily
IPR033742	IQSEC_PH	Domain
IPR035999	Sec7_dom_sf	Homologous_superfamily

Pfam: PF01369, PF16453

UniProt features (89 total): compositionally biased region 22, modified residue 19, helix 14, strand 9, region of interest 7, splice variant 5, sequence variant 5, domain 2, sequence conflict 2, turn 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9M46	X-RAY DIFFRACTION	1.77
6FAE	X-RAY DIFFRACTION	2.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5JU85-F1	54.46	0.22

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 (19): 82, 228, 344, 393, 412, 501, 528, 607, 627, 741, 744, 1107, 1129, 1143, 1158, 1161, 1172, 1173, 1345

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 505 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, AAGTCCA_MIR422B_MIR422A, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, TATTATA_MIR374, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, CACCAGC_MIR138, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY

GO Biological Process (7): actin cytoskeleton organization (GO:0030036), regulation of ARF protein signal transduction (GO:0032012), modulation of chemical synaptic transmission (GO:0050804), positive regulation of synapse assembly (GO:0051965), positive regulation of synaptic transmission, glutamatergic (GO:0051968), regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696), positive regulation of long-term synaptic depression (GO:1900454)

GO Molecular Function (2): guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), Schaffer collateral - CA1 synapse (GO:0098685)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeleton organization	1
actin filament-based process	1
ARF protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
synaptic transmission, glutamatergic	1
positive regulation of synaptic transmission	1
regulation of synaptic transmission, glutamatergic	1
regulation of biological quality	1
neurotransmitter receptor localization to postsynaptic specialization membrane	1
regulation of protein localization to synapse	1
regulation of receptor localization to synapse	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
positive regulation of biological process	1
long-term synaptic depression	1
regulation of long-term synaptic depression	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
synapse	1

Protein interactions and networks

STRING

1104 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IQSEC2	BAIAP2	Q9UQB8	827
IQSEC2	ARF1	P10947	756
IQSEC2	DLG4	P78352	752
IQSEC2	KDM5C	P41229	749
IQSEC2	SMC1A	Q14683	711
IQSEC2	GRIN2A	Q12879	638
IQSEC2	ARF6	P26438	613
IQSEC2	RABIF	P47224	607
IQSEC2	CDKL5	O76039	595
IQSEC2	DLG2	Q15700	591
IQSEC2	GRIN2B	Q13224	572
IQSEC2	DLG1	Q12959	557
IQSEC2	STXBP1	P61764	545
IQSEC2	KCNJ4	P48050	520
IQSEC2	PCDH19	Q8TAB3	505

IntAct

147 interactions, top by confidence:

A	B	Type	Score
APBA2	APP	psi-mi:“MI:0914”(association)	0.690
IQSEC2	APBA2	psi-mi:“MI:0407”(direct interaction)	0.690
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
DLG1	IQSEC2	psi-mi:“MI:0407”(direct interaction)	0.620
IQSEC2	DLG1	psi-mi:“MI:0407”(direct interaction)	0.620
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
CALM1	IQSEC2	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
APBA2	HERC2	psi-mi:“MI:0914”(association)	0.530
BAIAP2L1	IQSEC2	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC2	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (45): IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS), CCDC8 (Affinity Capture-MS), RAC1 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-RNA), IQSEC2 (Proximity Label-MS), IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS), IQSEC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JUG7, A1L390, E9Q0S6, O08774, O14924, O15085, O43182, O54834, O54960, O60307, O75052, P57095, Q13009, Q3U1V8, Q3U214, Q3UHC7, Q4VAC9, Q5DU25, Q5JU85, Q5RBI7, Q5SXA9, Q5VWQ8, Q60610, Q64512, Q6AX33, Q6DN90, Q6NXJ0, Q6P0Q8, Q6P1I6, Q6ZMN7, Q76G19, Q76LL6, Q76M68, Q7T2V3, Q810W7, Q8CGE9, Q8IX03, Q8R0S2, Q8R4H2, Q8WYP3

Diamond homologs: A0A0G2JUG7, A2A5R2, A5PKW4, D4A631, E1JIT7, F1MUS9, F4IXW2, F4JN05, F4JSZ5, F4K2K3, G3X9K3, G5EET6, O08967, O13690, O13817, O43739, O46382, P11075, P34512, P39993, P47102, P63034, P63035, P97694, P97696, Q10491, Q15438, Q2KI41, Q2PFD7, Q3TES0, Q42510, Q54KA7, Q5DTT2, Q5DU25, Q5E9G6, Q5JU85, Q6DFZ1, Q6DN90, Q6P1I6, Q76M68

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
IQSEC2	up-regulates	Excitatory_synaptic_transmission
IQSEC2	“up-regulates quantity”	GRIA1	relocalization
IQSEC2	“up-regulates quantity”	GRIA2	relocalization
IQSEC2	“up-regulates quantity”	GRIA3	relocalization
IQSEC2	“up-regulates quantity”	GRIA4	relocalization
IQSEC2	“up-regulates quantity”	AMPA	relocalization
IQSEC2	“up-regulates activity”	ARF6	“guanine nucleotide exchange factor”
IQSEC2	“up-regulates activity”	DLG4	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	57.1×	5e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	50.4×	7e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	50.4×	7e-08
Ras activation upon Ca2+ influx through NMDA receptor	6	42.8×	2e-07
Unblocking of NMDA receptors, glutamate binding and activation	6	40.8×	2e-07
Negative regulation of NMDA receptor-mediated neuronal transmission	6	40.8×	2e-07
Activation of BH3-only proteins	6	37.2×	3e-07
Long-term potentiation	6	35.7×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	57.1×	2e-14
protein localization to synapse	6	41.0×	1e-06
receptor clustering	7	39.0×	2e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	31.0×	6e-07
protein targeting	7	22.9×	3e-06
substantia nigra development	5	16.4×	7e-04
long-term synaptic potentiation	5	12.5×	2e-03
protein-containing complex assembly	9	9.2×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1521 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	159
Likely pathogenic	65
Uncertain significance	562
Likely benign	459
Benign	90

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069101	NM_001111125.3(IQSEC2):c.3611_3791del (p.Phe1204fs)	Pathogenic
1070778	NM_001111125.3(IQSEC2):c.3433C>T (p.Arg1145Ter)	Pathogenic
1071797	NM_001111125.3(IQSEC2):c.1925del (p.Pro642fs)	Pathogenic
1072485	NM_001111125.3(IQSEC2):c.2336_2337del (p.Gly779fs)	Pathogenic
1074866	NM_001111125.3(IQSEC2):c.3237del (p.Ile1080fs)	Pathogenic
1075324	NM_001111125.3(IQSEC2):c.3387C>G (p.Tyr1129Ter)	Pathogenic
1076348	NC_000023.10:g.(?53270946)(53271111_?)del	Pathogenic
1076522	NM_001111125.3(IQSEC2):c.4402_4418dup (p.Ser1474fs)	Pathogenic
1076577	NM_001111125.3(IQSEC2):c.3106C>T (p.Gln1036Ter)	Pathogenic
10863	NM_001111125.3(IQSEC2):c.2402A>C (p.Gln801Pro)	Pathogenic
10864	NM_001111125.3(IQSEC2):c.2273G>A (p.Arg758Gln)	Pathogenic
1098375	NM_001111125.3(IQSEC2):c.2292del (p.Phe764fs)	Pathogenic
1098384	NM_001111125.3(IQSEC2):c.2203C>T (p.Gln735Ter)	Pathogenic
1176938	NM_001111125.3(IQSEC2):c.828del (p.Ser277fs)	Pathogenic
1183997	NM_001111125.3(IQSEC2):c.3499G>T (p.Glu1167Ter)	Pathogenic
1209574	NM_001111125.3(IQSEC2):c.1049C>T (p.Ala350Val)	Pathogenic
1218675	NM_001111125.3(IQSEC2):c.3515dup (p.Ser1172fs)	Pathogenic
126415	NC_000023.11:g.53254331_53296102dup	Pathogenic
126416	NM_001243197.1(IQSEC2):c.123-2226_*20117dup	Pathogenic
126417	NM_001111125.3(IQSEC2):c.2563C>T (p.Arg855Ter)	Pathogenic
1285235	NM_001111125.3(IQSEC2):c.4264_4265del (p.Gln1422fs)	Pathogenic
1323121	NM_001111125.3(IQSEC2):c.2225G>A (p.Trp742Ter)	Pathogenic
1338309	NM_001111125.3(IQSEC2):c.3163C>T (p.Arg1055Ter)	Pathogenic
1361147	NM_001111125.3(IQSEC2):c.705delA (p.Lys236fs)	Pathogenic
1376143	NM_001111125.3(IQSEC2):c.627del (p.Ser210fs)	Pathogenic
1406772	NM_001111125.3(IQSEC2):c.2380G>T (p.Glu794Ter)	Pathogenic
1408417	NM_001111125.3(IQSEC2):c.4334del (p.Pro1445fs)	Pathogenic
1418285	NM_001111125.3(IQSEC2):c.1296T>G (p.Tyr432Ter)	Pathogenic
1452197	NM_001111125.3(IQSEC2):c.2305G>T (p.Glu769Ter)	Pathogenic
1454379	NM_001111125.3(IQSEC2):c.4410dup (p.Asn1471fs)	Pathogenic

SpliceAI

2469 predictions. Top by Δscore:

Variant	Effect	Δscore
X:53235781:A:AC	donor_gain	1.0000
X:53235782:C:CC	donor_gain	1.0000
X:53236316:GCTTA:G	donor_loss	1.0000
X:53236317:CTTA:C	donor_loss	1.0000
X:53236318:TTA:T	donor_loss	1.0000
X:53236319:TA:T	donor_loss	1.0000
X:53236320:A:AC	donor_gain	1.0000
X:53236320:A:AT	donor_loss	1.0000
X:53236321:C:CA	donor_loss	1.0000
X:53236321:C:CC	donor_gain	1.0000
X:53236321:CCTG:C	donor_gain	1.0000
X:53236491:CTCCG:C	acceptor_gain	1.0000
X:53236492:TCCG:T	acceptor_gain	1.0000
X:53236493:CCG:C	acceptor_gain	1.0000
X:53236493:CCGC:C	acceptor_gain	1.0000
X:53236494:CGC:C	acceptor_gain	1.0000
X:53236496:C:CC	acceptor_gain	1.0000
X:53236500:G:C	acceptor_gain	1.0000
X:53236500:G:GC	acceptor_gain	1.0000
X:53236504:C:CT	acceptor_gain	1.0000
X:53236505:A:T	acceptor_gain	1.0000
X:53236508:C:CT	acceptor_gain	1.0000
X:53236509:G:T	acceptor_gain	1.0000
X:53238140:CTCA:C	donor_loss	1.0000
X:53238142:CA:C	donor_loss	1.0000
X:53238143:A:AC	donor_gain	1.0000
X:53238143:AC:A	donor_loss	1.0000
X:53238143:ACACT:A	donor_gain	1.0000
X:53238144:C:CC	donor_gain	1.0000
X:53238144:CA:C	donor_gain	1.0000

AlphaMissense

9666 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:53238195:A:G	L1076P	1.000
X:53238207:A:G	F1072S	1.000
X:53238234:G:T	A1063D	1.000
X:53238240:A:G	F1061S	1.000
X:53238285:A:G	L1046S	1.000
X:53238294:C:T	G1043E	1.000
X:53238295:C:A	G1043W	1.000
X:53238295:C:G	G1043R	1.000
X:53238295:C:T	G1043R	1.000
X:53239286:T:A	K1008N	1.000
X:53239286:T:G	K1008N	1.000
X:53239287:T:A	K1008I	1.000
X:53239288:T:C	K1008E	1.000
X:53239293:A:T	V1006D	1.000
X:53241788:A:G	L1004P	1.000
X:53241788:A:T	L1004H	1.000
X:53241791:A:G	L1003P	1.000
X:53241794:T:A	D1002V	1.000
X:53241800:A:G	F1000S	1.000
X:53241805:G:C	F998L	1.000
X:53241805:G:T	F998L	1.000
X:53241806:A:G	F998S	1.000
X:53241807:A:G	F998L	1.000
X:53241809:A:T	V997D	1.000
X:53241866:A:G	L978P	1.000
X:53243417:C:G	R935P	1.000
X:53243424:A:C	Y933D	1.000
X:53243435:A:G	L929P	1.000
X:53243435:A:T	L929Q	1.000
X:53243450:A:C	I924S	1.000

dbSNP variants (sampled 300 via entrez): RS1000006341 (X:53293399 A>G), RS1000050954 (X:53297890 G>A,T), RS1000081651 (X:53312203 T>A), RS1000140984 (X:53307127 C>T), RS1000221272 (X:53232258 T>C), RS1000273695 (X:53231580 G>A), RS1000588953 (X:53295420 C>T), RS1000655644 (X:53297523 C>T), RS1000700698 (X:53251844 G>A,T), RS1000760458 (X:53240988 C>T), RS1000767834 (X:53316286 A>G), RS1000852202 (X:53261629 T>G), RS1000941523 (X:53241302 C>T), RS1001220904 (X:53235328 G>A,C), RS1001255641 (X:53299999 A>G)

Disease associations

OMIM: gene MIM:300522 | disease phenotypes: MIM:309530, MIM:300590, MIM:309560, MIM:301024, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 1	Definitive	X-linked
complex neurodevelopmental disorder	Definitive	X-linked
X-linked complex neurodevelopmental disorder	Definitive	X-linked
severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome	Supportive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (15): intellectual disability, X-linked 1 (MONDO:0010656), Cornelia de Lange syndrome 2 (MONDO:0010370), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), undetermined early-onset epileptic encephalopathy (MONDO:0018614), paraplegia-intellectual disability-hyperkeratosis syndrome (MONDO:0010662), intellectual developmental disorder, X-linked 108 (MONDO:0026723), autism (MONDO:0005260), specific learning disability (MONDO:0016225), autism spectrum disorder (MONDO:0005258), microcephaly (MONDO:0001149), complex neurodevelopmental disorder (MONDO:0100038), X-linked complex neurodevelopmental disorder (MONDO:0100148), (MONDO:0018347), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (8): X-linked non-syndromic intellectual disability (Orphanet:777), Cornelia de Lange syndrome (Orphanet:199), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Paraplegia-intellectual disability-hyperkeratosis syndrome (Orphanet:2824), Specific learning disability (Orphanet:211047), Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome (Orphanet:397933), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

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

HPO	Term
HP:0000069	Abnormality of the ureter
HP:0000119	Abnormality of the genitourinary system
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000204	Cleft upper lip
HP:0000220	Velopharyngeal insufficiency
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000321	Square face
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000400	Macrotia
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000540	Hypermetropia
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002398_34	Neutrophil count	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count

MeSH disease descriptors (9)

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
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
D000067559	Specific Learning Disorder	C10.597.606.150.550.700; C23.888.592.604.150.550.700; F03.625.374.188.700; F03.625.562.700
C537058	Fitzsimmons-McLachlan-Gilbert syndrome (supp.)
C567906	Mental Retardation, X-Linked 1 (supp.)
C564489	Mental Retardation, X-Linked 78 (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Atrazine	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SS82	HAP1 IQSEC2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

300 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,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
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
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
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