IQSEC2

Chr X

IQ motif and Sec7 domain ArfGEF 2

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

NCBI Gene: 23096 ENSG00000124313 UniProt: Q5JU85

The protein functions as a guanine nucleotide exchange factor for ARF GTP-binding proteins and is a component of the postsynaptic density at excitatory synapses, where it regulates cytoskeletal and synaptic organization through activation of ARF1 and ARF6. Mutations cause X-linked intellectual developmental disorder, predominantly through loss-of-function mechanisms given the gene's high constraint against such variants (pLI 0.999, LOEUF 0.133). The condition follows X-linked dominant inheritance.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.13

Clinical Summary— IQSEC2

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Gene-Disease Validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

226 unique Pathogenic / Likely Pathogenic· 564 VUS of 1512 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — IQSEC2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.03 (0.01–0.13)

0≤0.351.4

Missense OE?0.40 (0.36–0.45)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 1 / 35.6Missense obs/exp: 241 / 598.2Syn Z: 1.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveIQSEC2-related intellectual developmental disorderLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

0.3196th %ile

GOF

0.4481th %ile

LOF

0.83top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 85% of P/LP variants are LoF · LOEUF 0.13 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

1512 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic153

Likely Pathogenic73

VUS564

Likely Benign500

Benign86

Conflicting77

153

Pathogenic

Likely Pathogenic

564

VUS

500

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	140	8	5	0	153
Likely Pathogenic	52	17	3	1	73
VUS	6	523	27	8	564
Likely Benign	1	68	108	323	500
Benign	0	22	34	30	86
Conflicting	—				77
Total	199	638	177	362	1,453

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

View in ClinVar →

76 pathogenic / likely-pathogenic (of 88) ClinVar copy-number / structural variants overlap IQSEC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →