ARFGEF1

protein-coding

ADP ribosylation factor guanine nucleotide exchange factor 1, the group of Armadillo like helical domain containing|ARFGEF family

Gene summary

ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Aug 2011]

MANE transcript

NM_006421.5

Inheritance

ClinVar variants

P:79U:380B:63

Top phenotype

Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr8:67,173,511-67,343,781

External References & Databases

Ensembl (ENSG00000066777)

Transcript & Mutation Effects

hg38 • Region Span ~170.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859263

Submitter: Illumina

developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859263

Submitter: Labcorp Genetics (formerly Invitae)

schizophreniaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859263

Submitter: PanelApp Australia

developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859263

Submitter: ClinGen

*ARFGEF1* (ADP-Ribosylation Factor Guanine Nucleotide-Exchange Factor 1) is located at chromosome 8 at 8q13.2 and encodes a brefeldin A-sensitive guanine nucleotide exchange factor that activates ARF1 and ARF3 to promote vesicular trafficking and maintain Golgi structure. *ARFGEF1* was first reported in relation to autosomal dominant developmental delay, impaired speech, and behavioral abnormalities, with or without seizures in 2020 (Teoh et al., PMID: 31678406). Ten variants including 1 missense, 5 nonsense, 2 frameshift, and 2 essential splice site variants that have been reported in ten probands from three publications (PMIDs: 31678406, 34113008, 35782386) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is supported by experimental evidence including a heterozygous knockout mouse model which recapitulates the developmental delay and increased susceptibility to seizures observed in affected individuals (PMID: 31678406). In summary, there is definitive evidence supporting the relationship between *ARFGEF1* and autosomal dominant developmental delay, impaired speech, and behavioral abnormalities, with or without seizures. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic disease GCEP on the meeting date November 21, 2025 (SOP Version 11).

developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859263

Submitter: G2P

developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859263

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresAD

Manifestation: Craniofacial; Neurologic; Ophthalmologic

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: 31678406; 34113008

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARFGEF1 variants in ClinVar

18 Conditions Cataloged

not providedTotal: 258

Inborn genetic diseasesTotal: 152

Developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresTotal: 95

not specifiedTotal: 35

ARFGEF1-related disorderTotal: 28

Global developmental delayTotal: 10

Intellectual disabilityTotal: 10

Delayed speech and language developmentTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006421.5. 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			6 clinvar	36 clinvar	3 clinvar	45
missense	1 clinvar	6 clinvar	351 clinvar	21 clinvar	2 clinvar	381
nonsense	14 clinvar	10 clinvar	3 clinvar			27
start loss			1 clinvar			1
frameshift	17 clinvar	13 clinvar	7 clinvar			37
splice donor/acceptor (+/-2bp)	4 clinvar	14 clinvar	12 clinvar	1 clinvar		31
Total	36	43	380	58	5	522

Highest pathogenic variant AF is 0.000006865997

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006421.5	RefSeq	NP_006412.2	39	MANE Select
ENST00000262215.8	Ensembl	ENSP00000262215.3	39	MANE Select
NM_001413184.1	RefSeq	NP_001400113.1	39	Standard
NM_001413185.1	RefSeq	NP_001400114.1	39	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
thrombin signaling and protease-activated receptors
adp-ribosylation factor

Biological Process

exocytosis
Golgi organization
endomembrane system organization
protein transport
vesicle-mediated transport

Molecular Function

guanyl-nucleotide exchange factor activity
ARF guanyl-nucleotide exchange factor activity
GTPase activator activity
protein binding
myosin binding

Cellular Component

Golgi membrane
nucleoplasm
nucleolus
Golgi apparatus
trans-Golgi network

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262215
Coding exons: 39
Length: 170166
Individuals with no LoFs: 125662
Homozygous LoFs: 0
Heterozygous LoFs: 86
Defined: 125748
p: 0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.37	479	943	0.508	0.0000464	12216
Missense (PolyPhen)		118	383.68	0.30755		5103
Synonymous	-0.378	334	325	1.03	0.0000163	3401
Loss of Function	8.58	8	101	0.0792	0.00000530	1237

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0028	0.0026	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000081	0.000079	rare
South Asian	0.00053	0.00046	rare
Other	0.00053	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes guanine-nucleotide exchange on ARF1 and ARF3. Promotes the activation of ARF1/ARF3 through replacement of GDP with GTP. Involved in vesicular trafficking. Required for the maintenance of Golgi structure; the function may be independent of its GEF activity. Required for the maturaion of integrin beta-1 in the Golgi. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways. Inhibits GAP activity of MYO9B probably through competetive RhoA binding. The function in the nucleus remains to be determined. {ECO:0000269|PubMed:12571360, ECO:0000269|PubMed:15644318, ECO:0000269|PubMed:17227842, ECO:0000269|PubMed:20360857, ECO:0000269|PubMed:22084092}.;

Recessive Scores

pRec: 0.283

Intolerance Scores

LoFtool: 0.444
RVIS EVS: -1.75
RVIS percentile EVS: 2.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.839

Gene Damage Prediction

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