ARFGEF2

Chr 20AR

ARF guanine nucleotide exchange factor 2

Also known as: BIG2, PVNH2, dJ1164I10.1

NCBI Gene: 10564ENSG00000124198UniProt: Q9Y6D5

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 and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Periventricular heterotopia with microcephalyMIM #608097
AR
UniProtPeriventricular nodular heterotopia 2
265
ClinVar variants
10
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ARFGEF2
🧬
Gene-Disease Validity (ClinGen)
periventricular heterotopia with microcephaly, autosomal recessive · ARDefinitive

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
10 Pathogenic / Likely Pathogenic· 142 VUS of 265 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.25LOEUF
pLI 1.000
Z-score 7.65
OE 0.16 (0.11–0.25)
Highly constrained

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

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.
2.60Z-score
OE missense 0.76 (0.72–0.81)
731 obs / 957.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.16 (0.11–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.72–0.81)
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.0.94
0≤1.21.6
LoF obs/exp: 16 / 97.5Missense obs/exp: 731 / 957.1Syn Z: 0.82

ClinVar Variant Classifications

265 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic4
VUS142
Likely Benign100
Benign10
Conflicting3
6
Pathogenic
4
Likely Pathogenic
142
VUS
100
Likely Benign
10
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
4
0
6
Likely Pathogenic
1
0
3
0
4
VUS
0
132
9
1
142
Likely Benign
0
3
42
55
100
Benign
0
0
9
1
10
Conflicting
—3
Total31356757265

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

View in ClinVar →

Protein Context — Lollipop Plot

ARFGEF2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ARFGEF2-related periventricular heterotopia with microcephaly

strong
ARLoss 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

Periventricular heterotopia with microcephaly

MIM #608097

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: case study and literature review.
Tanyalçin I et al.·Eur J Paediatr Neurol
2013Review
Movement disorder and neuronal migration disorder due to ARFGEF2 mutation.
de Wit MC et al.·Neurogenetics
2009
Recognisable Neuroradiological Findings in Five Neurogenetic Disorders.
Rosenblum J et al.·Clin Genet
2025Review
Neuronal migration disorders: clinical, neuroradiologic and genetics aspects.
Spalice A et al.·Acta Paediatr
2009Review
Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations.
Parrini E et al.·Brain
2006
Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity.
Cellini E et al.·Eur J Hum Genet
2019Clinical trial
Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion.
Cardoso C et al.·Neurology
2009Case report
Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1.
Dworkis DA et al.·Am J Hematol
2011
Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene.
Conti V et al.·Brain
2013
Genetic modifiers of response to glucose-insulin-potassium (GIK) infusion in acute coronary syndromes and associations with clinical outcomes in the IMMEDIATE trial.
Ellis KL et al.·Pharmacogenomics J
2015Clinical trial
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools