IQSEC1

Summary

IQSEC1 (IQ motif and Sec7 domain ArfGEF 1, HGNC:29112) is a protein-coding gene on chromosome 3p25.2, encoding IQ motif and SEC7 domain-containing protein 1 (Q6DN90). Guanine nucleotide exchange factor for ARF1 and ARF6.

Predicted to enable protein kinase binding activity. Predicted to be involved in several processes, including positive regulation of focal adhesion disassembly; positive regulation of keratinocyte migration; and regulation of postsynaptic neurotransmitter receptor internalization. Located in centrosome; cytosol; and nucleoplasm. Implicated in intellectual developmental disorder with short stature and behavioral abnormalities and lung adenocarcinoma. Biomarker of lung non-small cell carcinoma.

Source: NCBI Gene 9922 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder with short stature and behavioral abnormalities (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 292 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 15
• MANE Select transcript: NM_001134382

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29112
Approved symbol	IQSEC1
Name	IQ motif and Sec7 domain ArfGEF 1
Location	3p25.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0763, GEP100, BRAG2, ARF-GEP100
Ensembl gene	ENSG00000144711
Ensembl biotype	protein_coding
OMIM	610166
Entrez	9922

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000273221, ENST00000473088, ENST00000474467, ENST00000613206, ENST00000618604, ENST00000646269, ENST00000647458, ENST00000648114, ENST00000648386, ENST00000707112

RefSeq mRNA: 4 — MANE Select: NM_001134382 NM_001134382, NM_001330619, NM_001376938, NM_014869

CCDS: CCDS33703, CCDS74902, CCDS87048, CCDS93218

Canonical transcript exons

ENST00000613206 — 14 exons

Exon	Start	End
ENSE00000966677	12920430	12920596
ENSE00000966678	12915594	12915733
ENSE00000966679	12915104	12915133
ENSE00000966680	12913428	12913553
ENSE00000966681	12911629	12911728
ENSE00000966682	12909273	12909434
ENSE00000966683	12908349	12908525
ENSE00000966684	12902773	12902822
ENSE00001386378	12935448	12936697
ENSE00001663115	12924581	12924742
ENSE00001729128	12922120	12922242
ENSE00003539805	12941571	12941865
ENSE00003737071	13072992	13073429
ENSE00003748668	12897043	12901522

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 96.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.3677 / max 209.0453, expressed in 1745 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41146	4.6931	1447
41183	2.5688	623
41179	1.7031	353
41169	1.3337	214
41174	0.7937	125
41153	0.7507	433
41181	0.6536	226
41184	0.6264	293
41152	0.5578	315
41154	0.4885	283

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 46	UBERON:0006483	96.90	gold quality
postcentral gyrus	UBERON:0002581	96.65	gold quality
parietal lobe	UBERON:0001872	96.42	gold quality
superior frontal gyrus	UBERON:0002661	96.40	gold quality
right frontal lobe	UBERON:0002810	96.39	gold quality
prefrontal cortex	UBERON:0000451	96.36	gold quality
frontal cortex	UBERON:0001870	96.14	gold quality
frontal lobe	UBERON:0016525	96.14	gold quality
cingulate cortex	UBERON:0003027	95.93	gold quality
anterior cingulate cortex	UBERON:0009835	95.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.79	gold quality
neocortex	UBERON:0001950	95.70	gold quality
middle temporal gyrus	UBERON:0002771	95.60	gold quality
primary visual cortex	UBERON:0002436	95.32	gold quality
orbitofrontal cortex	UBERON:0004167	95.24	gold quality
entorhinal cortex	UBERON:0002728	95.19	gold quality
cerebral cortex	UBERON:0000956	95.16	gold quality
tibia	UBERON:0000979	95.03	gold quality
endothelial cell	CL:0000115	95.00	gold quality
occipital lobe	UBERON:0002021	94.93	gold quality
blood	UBERON:0000178	94.53	gold quality
temporal lobe	UBERON:0001871	94.31	gold quality
telencephalon	UBERON:0001893	94.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.98	gold quality
amygdala	UBERON:0001876	93.89	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.72	gold quality
CA1 field of hippocampus	UBERON:0003881	93.64	gold quality
Ammon’s horn	UBERON:0001954	93.61	gold quality
inferior olivary complex	UBERON:0002127	93.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting IQSEC1, 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-4692	100.00	67.32	2066
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-204-5P	99.79	71.62	2439

Literature-anchored findings (GeneRIF, showing 21)

• Arf6 regulates both endocytosis and recycling of beta1 integrins and BRAG2 (IQSEC1) functions selectively to activate Arf6 during integrin internalization (PMID:16461286)
• Guanine nucleotide-exchange protein (GEP) 100/BRAG2 has an important role in the activation of ADP-ribosylation factor (ARF)6 for its functions in both E-cadherin recycling and actin remodeling. (PMID:16807291)
• Results indicate that GEP100 links EGFR signalling to Arf6 activation to induce invasive activities of some breast cancer cells, and hence may contribute to their metastasis and malignancy. (PMID:18084281)
• GEP100 functions in phagocytosis via its role in ARF6-dependent actin remodeling. (PMID:20601426)
• a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration. (PMID:21795701)
• Data suggest that GEP100-Arf6-AMAP1-cortactin pathway, activated by VEGFR2, appears to be common in angiogenesis and cancer invasion and metastasis, and provides their new therapeutic targets. (PMID:21858086)
• Cinical study indicates that co-overexpression of Her2 with GEP100 in primary lung adenocarcinomas of patients is correlated with the presence of their node-metastasis with a statistical significance. (PMID:21966491)
• The PH domain and the interdomain linker of Brag2 may be targets for selectively regulating the activity of Brag2. (PMID:22613714)
• GEP100 plays a significant role in pancreatic cancer invasion through regulating the expression of E-cadherin and the process of mesenchymal to epithelial transition (MET). (PMID:22662237)
• GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells. (PMID:22701712)
• BRAG2 acts at clathrin-coated pits to promote integrin internalization by activating Arf5 and suggest a previously unrecognized role for Arf5 in clathrin-mediated endocytosis of specific cargoes. (PMID:22815487)
• GEP100 regulates an Arf6/ERK/uPAR signaling cascade in EGF-induced breast cancer cell invasion. (PMID:23747719)
• Data show that co-overexpression of GEP100 and AMAP1 (ASAP1) correlates with rapidity of the local recurrence. (PMID:24116160)
• Brag2 is essential for developmental and pathological angiogenesis by promoting endothelial cell sprouting through regulation of adhesion by beta1-integrin internalization and link for the first time the process of beta1-integrin endocytosis with angiogenesis. (PMID:24522833)
• The EGFR-GEP100-Arf6 axis affected the prognosis of patients with primary lung adenocarcinoma. (PMID:24902879)
• 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)
• IQSEC1 variants are the cause of a recessive disease with intellectual disability. (PMID:31607425)
• Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex. (PMID:32234213)
• An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism. (PMID:33712589)
• circ-Iqsec1 induces bone marrow-derived mesenchymal stem cell (BMSC) osteogenic differentiation through the miR-187-3p/Satb2 signaling pathway. (PMID:36517907)
• Contribution of gene polymorphisms on 3p25 to salivary gland carcinoma, ameloblastoma, and odontogenic keratocyst in the Chinese Han population. (PMID:37495273)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	iqsec1b	ENSDARG00000016551
danio_rerio	IQSEC1	ENSDARG00000073822
mus_musculus	Iqsec1	ENSMUSG00000034312
rattus_norvegicus	Iqsec1	ENSRNOG00000060350
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), IQSEC2 (ENSG00000124313), PSD4 (ENSG00000125637), PSD2 (ENSG00000146005), PSD3 (ENSG00000156011), FBXO8 (ENSG00000164117)

Protein

Protein identifiers

IQ motif and SEC7 domain-containing protein 1 — Q6DN90 (reviewed: Q6DN90)

Alternative names: ADP-ribosylation factors guanine nucleotide-exchange protein 100, ADP-ribosylation factors guanine nucleotide-exchange protein 2, Brefeldin-resistant Arf-GEF 2 protein

All UniProt accessions (7): Q6DN90, A0A0C4DGT3, A0A2R8Y695, A0A2R8Y7T6, A0A3B3IRZ4, A0A3B3IU98, A0A9L9PXV7

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor for ARF1 and ARF6. Guanine nucleotide exchange factor activity is enhanced by lipid binding. Accelerates GTP binding by ARFs of all three classes. Guanine nucleotide exchange protein for ARF6, mediating internalization of beta-1 integrin. Involved in neuronal development. In neurons, plays a role in the control of vesicle formation by endocytoc cargo. Upon long term depression, interacts with GRIA2 and mediates the activation of ARF6 to internalize synaptic AMPAR receptors.

Subunit / interactions. Interacts with ARF1 and ARF6. Interacts with GRIA2; the interaction is required for ARF6 activation.

Subcellular location. Cytoplasm. Nucleus. Postsynaptic density. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle.

Tissue specificity. Expressed in brain, ovary, heart, lung, liver, kidney and leukocytes. Moderate expression was also detected in lung, skeletal muscle, placenta, small intestine, pancreas, spleen and testis.

Disease relevance. Intellectual developmental disorder with short stature and behavioral abnormalities (IDDSSBA) [MIM:618687] An autosomal recessive disorder with onset in infancy and characterized by intellectual disability, developmental delay, short stature, aphasia, and hypotonia. Additional features include seizures and behavioral abnormalities, such as inattention, hyperactivity and aggression. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PH domain mediates interaction with lipid membranes that contain phosphatidylinositol-4,5-bisphosphate, but does not bind membranes that lack phosphatidylinositol-4,5-bisphosphate.

Similarity. Belongs to the BRAG family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6DN90-1	1, BRAG2b	yes
Q6DN90-2	2, BRAG2a
Q6DN90-3	3

RefSeq proteins (4): NP_001127854, NP_001317548, NP_001363867, NP_055684 (=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 (63 total): helix 17, modified residue 12, strand 9, compositionally biased region 4, sequence variant 4, region of interest 4, domain 3, splice variant 3, turn 3, chain 1, mutagenesis site 1, sequence conflict 1, coiled-coil region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7VMB	X-RAY DIFFRACTION	2
5NLY	X-RAY DIFFRACTION	2
3QWM	X-RAY DIFFRACTION	2.39
5NLV	X-RAY DIFFRACTION	2.4
6FNE	X-RAY DIFFRACTION	2.5
4C0A	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6DN90-F1	63.61	0.35

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 (12): 89, 105, 107, 180, 249, 253, 512, 515, 892, 911, 924, 925

Mutagenesis-validated functional residues (1):

Position	Phenotype
620	abolishes guanosine nucleotide exchange factor activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 281 (showing top): GOBP_DENDRITE_DEVELOPMENT, FXR_IR1_Q6, MODULE_451, GCANCTGNY_MYOD_Q6, MODULE_45, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, MODULE_66, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (5): actin cytoskeleton organization (GO:0030036), regulation of ARF protein signal transduction (GO:0032012), positive regulation of keratinocyte migration (GO:0051549), dendritic spine development (GO:0060996), positive regulation of focal adhesion disassembly (GO:0120183)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), lipid binding (GO:0008289), protein binding (GO:0005515)

GO Cellular Component (10): nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), synaptic vesicle (GO:0008021), postsynaptic density (GO:0014069), membrane (GO:0016020), nucleus (GO:0005634), cytoplasm (GO:0005737), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	2
cytoplasm	2
cytoskeleton organization	1
actin filament-based process	1
ARF protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
positive regulation of epithelial cell migration	1
keratinocyte migration	1
regulation of keratinocyte migration	1
dendrite development	1
anatomical structure development	1
focal adhesion disassembly	1
regulation of focal adhesion disassembly	1
positive regulation of cell-substrate junction organization	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
nuclear lumen	1
centriole	1
microtubule organizing center	1
exocytic vesicle	1
presynapse	1
asymmetric synapse	1
postsynaptic specialization	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IQSEC1	ARF6	P26438	905
IQSEC1	ARF1	P10947	902
IQSEC1	ARF5	P26437	830
IQSEC1	EGFR	P00533	785
IQSEC1	ASAP1	Q9ULH1	726
IQSEC1	GRIA2	P42262	615
IQSEC1	DLG4	P78352	596
IQSEC1	PLEK2	Q9NYT0	593
IQSEC1	PLEK	P08567	585
IQSEC1	HGF	P14210	558
IQSEC1	CGGBP1	Q9UFW8	555
IQSEC1	CTNNA1	P35221	546
IQSEC1	RRAS	P10301	539
IQSEC1	RABIF	P47224	523
IQSEC1	CHST15	Q7LFX5	518

IntAct

129 interactions, top by confidence:

A	B	Type	Score
ANKRD28	PPP6C	psi-mi:“MI:0914”(association)	0.870
APBA2	APP	psi-mi:“MI:0914”(association)	0.690
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
SKP2	DPYSL4	psi-mi:“MI:0914”(association)	0.530
MLLT6	RGPD8	psi-mi:“MI:0914”(association)	0.530
APBA2	HERC2	psi-mi:“MI:0914”(association)	0.530
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
INSYN2A	CHUK	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
TFDP3	E2F3	psi-mi:“MI:0914”(association)	0.530
IRF7	AIP	psi-mi:“MI:0914”(association)	0.500
IQSEC1	ALS2	psi-mi:“MI:2364”(proximity)	0.470
IQSEC1	DCTN1	psi-mi:“MI:2364”(proximity)	0.470
IQSEC1	SOD1	psi-mi:“MI:2364”(proximity)	0.470
IQSEC1	TARDBP	psi-mi:“MI:2364”(proximity)	0.470
IQSEC1	DCTN1	psi-mi:“MI:0915”(physical association)	0.470
IQSEC1	SOD1	psi-mi:“MI:0915”(physical association)	0.470
IQSEC1	ALS2	psi-mi:“MI:0915”(physical association)	0.470
IQSEC1	TARDBP	psi-mi:“MI:0915”(physical association)	0.470
ARF6	IQSEC1	psi-mi:“MI:0407”(direct interaction)	0.440
IQSEC1	DLG1	psi-mi:“MI:0915”(physical association)	0.400
IQSEC1	GNAQ	psi-mi:“MI:0915”(physical association)	0.400
TOR1A	IQSEC1	psi-mi:“MI:0915”(physical association)	0.400
PRKN	IQSEC1	psi-mi:“MI:0915”(physical association)	0.400
IQSEC2	IQSEC1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (112): IQSEC1 (Affinity Capture-MS), IQSEC1 (Affinity Capture-MS), IQSEC1 (Proximity Label-MS), IQSEC1 (Proximity Label-MS), IQSEC1 (Affinity Capture-MS), IQSEC1 (Affinity Capture-MS), CTNNA1 (Two-hybrid), IQSEC1 (Affinity Capture-Western), CTNNA1 (Affinity Capture-Western), ARF6 (Co-fractionation), IQSEC1 (Affinity Capture-MS), IQSEC1 (Affinity Capture-MS), IQSEC1 (Affinity Capture-MS), IQSEC1 (Affinity Capture-MS), IQSEC1 (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

1 interactions.

A	Effect	B	Mechanism
MAP4K4	“up-regulates activity”		phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	207
Likely benign	47
Benign	9

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
695122	NM_001134382.3(IQSEC1):c.1028C>T (p.Thr343Met)	Pathogenic
1331647	NM_001134382.3(IQSEC1):c.1470dup (p.Tyr491fs)	Likely pathogenic
695123	NM_001134382.3(IQSEC1):c.962G>A (p.Arg321Gln)	Likely pathogenic

SpliceAI

3235 predictions. Top by Δscore:

Variant	Effect	Δscore
3:12901394:C:A	donor_gain	1.0000
3:12908343:TCTTA:T	donor_loss	1.0000
3:12908344:CTTA:C	donor_loss	1.0000
3:12908345:TTA:T	donor_loss	1.0000
3:12908346:TACCG:T	donor_loss	1.0000
3:12908347:A:AC	donor_gain	1.0000
3:12908347:A:C	donor_loss	1.0000
3:12908348:C:CC	donor_gain	1.0000
3:12908348:CCGG:C	donor_gain	1.0000
3:12908521:CTCCG:C	acceptor_gain	1.0000
3:12908523:CCG:C	acceptor_gain	1.0000
3:12908524:CGC:C	acceptor_gain	1.0000
3:12908526:C:CC	acceptor_gain	1.0000
3:12909272:CA:C	donor_gain	1.0000
3:12909272:CACT:C	donor_gain	1.0000
3:12911622:GACTT:G	donor_loss	1.0000
3:12911623:ACTT:A	donor_loss	1.0000
3:12911624:CTTA:C	donor_loss	1.0000
3:12911627:A:AC	donor_gain	1.0000
3:12911628:C:CA	donor_loss	1.0000
3:12911628:C:CC	donor_gain	1.0000
3:12911628:CA:C	donor_gain	1.0000
3:12911628:CACT:C	donor_gain	1.0000
3:12911628:CACTG:C	donor_gain	1.0000
3:12911729:C:CC	acceptor_gain	1.0000
3:12911729:C:CG	acceptor_loss	1.0000
3:12915146:G:C	acceptor_gain	1.0000
3:12915146:G:GC	acceptor_gain	1.0000
3:12915593:CCGG:C	donor_gain	1.0000
3:12920424:GCTCA:G	donor_loss	1.0000

AlphaMissense

7306 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:12909323:A:G	L857P	1.000
3:12909335:A:G	F853S	1.000
3:12909368:A:G	F842S	1.000
3:12911689:A:C	Y800D	1.000
3:12913432:A:G	L785P	1.000
3:12913435:A:G	L784P	1.000
3:12913447:A:G	L780P	1.000
3:12913449:G:C	F779L	1.000
3:12913449:G:T	F779L	1.000
3:12913450:A:G	F779S	1.000
3:12913451:A:G	F779L	1.000
3:12913459:C:G	R776P	1.000
3:12913501:A:T	V762D	1.000
3:12913510:A:G	L759P	1.000
3:12913528:A:G	L753S	1.000
3:12920435:A:G	L686P	1.000
3:12920447:A:G	F682S	1.000
3:12920462:A:G	M677T	1.000
3:12920507:A:G	L662P	1.000
3:12920510:A:G	L661P	1.000
3:12920519:G:T	A658D	1.000
3:12920521:G:C	F657L	1.000
3:12920521:G:T	F657L	1.000
3:12920522:A:G	F657S	1.000
3:12920523:A:G	F657L	1.000
3:12920528:A:G	L655P	1.000
3:12920533:G:C	F653L	1.000
3:12920533:G:T	F653L	1.000
3:12920535:A:G	F653L	1.000
3:12920589:A:C	Y635D	1.000

dbSNP variants (sampled 300 via entrez): RS1000007090 (3:12999738 G>A), RS1000010328 (3:13240076 A>T), RS1000010954 (3:12970082 G>A), RS1000042867 (3:13234379 G>A), RS1000051637 (3:13197645 A>G), RS1000058316 (3:12927952 G>A), RS1000065425 (3:13275969 T>C), RS1000065636 (3:12963549 A>C,G,T), RS1000072018 (3:13122275 C>T), RS1000072737 (3:13159394 A>G,T), RS1000077694 (3:13116202 G>C,T), RS1000078575 (3:13044822 C>A), RS1000083253 (3:12907604 G>A), RS1000083532 (3:13080192 T>C), RS1000092258 (3:13006966 T>C)

Disease associations

OMIM: gene MIM:610166 | disease phenotypes: MIM:618687

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with short stature and behavioral abnormalities	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

Mondo (2): intellectual developmental disorder with short stature and behavioral abnormalities (MONDO:0032870), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (0):

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000505	Visual impairment
HP:0000718	Aggressive behavior
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001344	Absent speech
HP:0002066	Gait ataxia
HP:0002133	Status epilepticus
HP:0004322	Short stature
HP:0007018	Attention deficit hyperactivity disorder
HP:0010864	Severe intellectual disability
HP:0031936	Delayed ability to walk

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002129_10	Periodontitis (DPAL)	1.000000e-06
GCST005951_48	Body mass index	5.000000e-08
GCST005956_72	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005957_11	Waist-to-hip ratio adjusted for BMI (age <50)	9.000000e-06
GCST005958_19	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-06
GCST005962_29	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	9.000000e-09
GCST011687_4	Systolic blood pressure	1.000000e-07
GCST012137_7	Motor coordination	3.000000e-06
GCST012616_9	Spondylosis	4.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0006335	systolic blood pressure
EFO:0010749	motor function measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	7
sodium arsenite	increases expression, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression	2
Ozone	affects cotreatment, increases expression, increases abundance, affects expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, increases methylation	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	decreases methylation	1
cobaltous chloride	decreases expression	1
nickel chloride	increases expression	1
zinc chromate	increases abundance, decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SS80	HAP1 IQSEC1 (-) 1	Cancer cell line	Male
CVCL_SS81	HAP1 IQSEC1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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