IQSEC2

Chr XXLD

IQ motif and Sec7 domain ArfGEF 2

Also known as: BRAG1, IQ-ArfGEF, MRX1, MRX18, MRX78, XLID1

NCBI Gene: 23096ENSG00000124313UniProt: Q5JU85

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. [provided by RefSeq, Aug 2011]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked 1MIM #309530
XLD
541
ClinVar variants
100
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— IQSEC2
🧬
Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
100 Pathogenic / Likely Pathogenic· 230 VUS of 541 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.13LOEUF
pLI 1.000
Z-score 5.37
OE 0.03 (0.01–0.13)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
5.19Z-score
OE missense 0.40 (0.36–0.45)
241 obs / 598.2 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.40 (0.36–0.45)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.85
0≤1.21.6
LoF obs/exp: 1 / 35.6Missense obs/exp: 241 / 598.2Syn Z: 1.91

ClinVar Variant Classifications

541 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic76
Likely Pathogenic24
VUS230
Likely Benign169
Benign23
Conflicting19
76
Pathogenic
24
Likely Pathogenic
230
VUS
169
Likely Benign
23
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
36
3
37
0
76
Likely Pathogenic
10
6
8
0
24
VUS
3
209
17
1
230
Likely Benign
1
25
46
97
169
Benign
0
6
4
13
23
Conflicting
—19
Total50249112111541

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

IQSEC2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

IQSEC2-related intellectual developmental disorder

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked 1

MIM #309530

Molecular basis of disorder known

X-linked dominant
📖
GeneReview available — IQSEC2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
X-Linked Epilepsies: A Narrative Review.
Bernardo P et al.·Int J Mol Sci
2024Review
IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy.
Shoubridge C et al.·Hum Mutat
2019Review
Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions.
Bai G et al.·J Cell Biol
2023
Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females.
Jackson MR et al.·Life Sci Alliance
2019
Epilepsy phenotypes across the different age-ranges in IQSEC2-related encephalopathy: An Italian multicentre retrospective cohort study.
Mastrangelo M et al.·Seizure
2024Cohort
Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy.
Wayhelova M et al.·Neurogenetics
2020Case report
IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?
Lopergolo D et al.·Clin Genet
2021
Genotype-phenotype correlation: Inheritance and variant-type infer pathogenicity in IQSEC2 gene.
Barrie ES et al.·Eur J Med Genet
2020Case report
[Clinical features and genetic analysis of 17 Chinese pedigrees affected with X-linked intellectual disability].
Li Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2024
IQSEC2-related encephalopathy in males due to missense variants in the pleckstrin homology domain.
Shoubridge C et al.·Clin Genet
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools