ARFGEF1

Chr 8

ARF guanine nucleotide exchange factor 1

Also known as: ARFGEP1, BIG1, DEDISB, P200

NCBI Gene: 10565 ENSG00000066777 UniProt: Q9Y6D6

The protein encoded by ARFGEF1 promotes guanine-nucleotide exchange on ARF1 and ARF3 to activate these proteins for vesicular trafficking, maintains Golgi structure, and is required for integrin beta-1 maturation. Mutations cause autosomal dominant developmental delay, impaired speech, and behavioral abnormalities with or without seizures. This gene is highly constrained against loss-of-function variants (pLI >0.99), indicating that functional copies are critical for normal development.

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. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Aug 2011]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.14

Clinical Summary— ARFGEF1

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Gene-Disease Validity (ClinGen)

developmental delay, impaired speech, and behavioral abnormalities, with or without seizures · ADDefinitive

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

82 unique Pathogenic / Likely Pathogenic· 450 VUS of 753 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.14LOEUF

pLI 1.000

Z-score 8.58

OE 0.08 (0.04–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.37Z-score

OE missense 0.51 (0.47–0.55)

479 obs / 942.9 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.14)

0≤0.351.4

Missense OE?0.51 (0.47–0.55)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 8 / 101.1Missense obs/exp: 479 / 942.9Syn Z: -0.38

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongARFGEF1-related intellectual disability and epilepsyLOFAD

This gene — mechanism propensity

0.3693th %ile

GOF

0.5170th %ile

LOF

0.65top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 90% of P/LP variants are LoF · LOEUF 0.14

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

753 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46

Likely Pathogenic36

VUS450

Likely Benign146

Benign24

Conflicting5

Pathogenic

Likely Pathogenic

450

VUS

146

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	43	1	2	0	46
Likely Pathogenic	31	5	0	0	36
VUS	28	396	23	3	450
Likely Benign	0	23	55	68	146
Benign	0	3	14	7	24
Conflicting	—				5
Total	102	428	94	78	707

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap ARFGEF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →