IQSEC1

Chr 3AR

IQ motif and Sec7 domain ArfGEF 1

Also known as: ARF-GEP100, ARFGEP100, BRAG2, GEP100, IDDSSBA

NCBI Gene: 9922 ENSG00000144711 UniProt: Q6DN90 OMIM: 610166

IQSEC1 encodes a guanine nucleotide exchange factor for ARF proteins that regulates vesicle formation and AMPA receptor internalization at synapses. Biallelic mutations cause autosomal recessive intellectual developmental disorder with short stature and behavioral abnormalities. This gene is highly constrained against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.221 OMIM phenotype

Clinical Summary— IQSEC1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ARLimited

Limited evidence — not for standalone diagnostic reporting

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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

3 unique Pathogenic / Likely Pathogenic· 208 VUS of 293 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 1.000

Z-score 5.34

OE 0.10 (0.05–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.28Z-score

OE missense 0.75 (0.70–0.81)

496 obs / 660.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.22)

0≤0.351.4

Missense OE?0.75 (0.70–0.81)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 4 / 40.8Missense obs/exp: 496 / 660.9Syn Z: -0.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongIQSEC1-related intellectual disability, developmental delay, and short statureOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4289th %ile

GOF

0.5169th %ile

LOF

0.71top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

293 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS208

Likely Benign52

Benign9

Conflicting1

Pathogenic

Likely Pathogenic

208

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	1	1	0	0	2
VUS	2	205	1	0	208
Likely Benign	0	8	3	41	52
Benign	0	4	1	4	9
Conflicting	—				1
Total	3	219	5	45	273

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap IQSEC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →