ARFGEF2

Chr 20AR

ARF guanine nucleotide exchange factor 2

Also known as: BIG2, PVNH2, dJ1164I10.1

NCBI Gene: 10564 ENSG00000124198 UniProt: Q9Y6D5 OMIM: 605371

This protein functions as a guanine nucleotide exchange factor that activates ARF proteins to regulate vesicular trafficking between the Golgi, endosomes, and plasma membrane. Biallelic mutations cause autosomal recessive periventricular heterotopia with microcephaly. The gene is highly constrained against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.251 OMIM phenotype

Clinical Summary— ARFGEF2

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Gene-Disease Validity (ClinGen)

periventricular heterotopia with microcephaly, autosomal recessive · ARDefinitive

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

27 unique Pathogenic / Likely Pathogenic· 420 VUS of 885 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.16 (0.11–0.25)

0≤0.351.4

Missense OE?0.76 (0.72–0.81)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 16 / 97.5Missense obs/exp: 731 / 957.1Syn Z: 0.82

ClinVar Variant Classifications

885 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16

Likely Pathogenic11

VUS420

Likely Benign272

Benign83

Conflicting50

Pathogenic

Likely Pathogenic

420

VUS

272

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	0	0	0	16
Likely Pathogenic	10	0	1	0	11
VUS	1	332	75	12	420
Likely Benign	0	4	138	130	272
Benign	0	0	78	5	83
Conflicting	—				50
Total	27	336	292	147	852

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap ARFGEF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →