IQSEC1

protein-coding

IQ motif and Sec7 domain ArfGEF 1, the group of IQSEC ArfGEF family

Gene summary

Predicted to enable guanyl-nucleotide exchange factor activity and 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 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, Jun 2026]

MANE transcript

NM_001134382.3

Inheritance

ClinVar variants

P:3U:217B:67

Top phenotype

Intellectual developmental disorder with short stature and behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr3:12,897,043-13,283,281

External References & Databases

Ensembl (ENSG00000144711)

Transcript & Mutation Effects

hg38 • Region Span ~386.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder with short stature and behavioral abnormalitiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032870

Submitter: Ambry Genetics

intellectual developmental disorder with short stature and behavioral abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032870

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*IQSEC1* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2019 (PMID: 31607425). The core phenotype observed in all reported cases includes severe intellectual disability, short stature, speech impairment, facial dysmorphia, and behavioral problems. Four variants (three missense and one frameshift) that have been reported in three probands in two publications (PMIDs: 31607425, 41738068) are included in this curation. Of note, two unrelated probands reported in 2019 with two novel missense variants curated here (PMID: 31607425) are from consanguineous families with affected siblings that have the same clinical phenotype and homozygous *IQSEC1* variants that were identified by exome sequencing. The mechanism of pathogenicity is reported to be loss- or partial loss-of-function. This gene-disease relationship is also supported by experimental evidence, including a mouse model with a conditional *Iqsec1* deletion in neurons that displayed increased dendritic spine density and immature morphology (PMID: 31607425). In summary, there is limited evidence supporting the relationship between *IQSEC1* and complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date April 21, 2026 (SOP Version 12).

intellectual developmental disorder with short stature and behavioral abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032870

Submitter: G2P

intellectual developmental disorder with short stature and behavioral abnormalitiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032870

Submitter: Ambry Genetics

intellectual developmental disorder with short stature and behavioral abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032870

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder with short stature and behavioral abnormalitiesAR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31607425

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IQSEC1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 215

not providedTotal: 69

Intellectual developmental disorder with short stature and behavioral abnormalitiesTotal: 15

IQSEC1-related disorderTotal: 4

Neurodevelopmental abnormalityTotal: 1

Developmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001134382.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	50 clinvar	4 clinvar	57
missense	1 clinvar	1 clinvar	208 clinvar	11 clinvar	2 clinvar	223
nonsense			3 clinvar			3
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	2	217	61	6	287

Highest pathogenic variant AF is 0.000014325487

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001134382.3	RefSeq	NP_001127854.1	14	MANE Select
ENST00000613206.2	Ensembl	ENSP00000480301.1	14	MANE Select
NM_001330619.3	RefSeq	NP_001317548.1	11	Standard
NM_001376938.2	RefSeq	NP_001363867.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
iqsec1a	Danio rerio	Structure: vascular lymphangioblast Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

iqsec1a

Danio rerio

Structure: vascular lymphangioblast

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
EGF-EGFR Signaling Pathway
Plexin-D1 Signaling
Arf6 signaling events

Biological Process

actin cytoskeleton organization
regulation of ARF protein signal transduction
positive regulation of GTPase activity
positive regulation of keratinocyte migration
positive regulation of adherens junction organization

Molecular Function

ARF guanyl-nucleotide exchange factor activity
protein binding
lipid binding

Cellular Component

nucleolus
cytoplasm
membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273221
Coding exons: 14
Length: 175899
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125746
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.28	496	661	0.750	0.0000481	6247
Missense (PolyPhen)		147	251.14	0.58534		2327
Synonymous	-0.112	294	292	1.01	0.0000220	1953
Loss of Function	5.34	4	40.8	0.0980	0.00000208	463

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000054	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide exchange factor for ARF1 and ARF6 (PubMed:24058294). Guanine nucleotide exchange factor activity is enhanced by lipid binding (PubMed:24058294). Accelerates GTP binding by ARFs of all three classes. Guanine nucleotide exchange protein for ARF6, mediating internalisation of beta-1 integrin. {ECO:0000269|PubMed:11226253, ECO:0000269|PubMed:16461286, ECO:0000269|PubMed:24058294}.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.159
RVIS EVS: -1.26
RVIS percentile EVS: 5.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.207

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium