ARF3

Chr 12

ARF GTPase 3

NCBI Gene: 377 ENSG00000134287 UniProt: P61204 OMIM: 103190

ADP-ribosylation factor 3 encodes a small GTP-binding protein that regulates vesicle trafficking and modulates vesicle budding and uncoating within the Golgi apparatus. Mutations cause autosomal recessive periventricular nodular heterotopia with intellectual disability and seizures, typically presenting in infancy with developmental delays and brain malformations affecting neuronal migration.

OMIM ResearchSummary from RefSeq, UniProt

ADP-ribosylation factor 3 (ARF3) is a member of the human ARF gene family. These genes encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking and as activators of phospholipase D. The gene products include 6 ARF proteins and 11 ARF-like proteins and constitute one family of the RAS superfamily. The ARF proteins are categorized as class I (ARF1, ARF2,and ARF3), class II (ARF4 and ARF5) and class III (ARF6) and members of each class share a common gene organization. [provided by RefSeq, Oct 2022]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.72

Clinical Summary— ARF3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 17 VUS of 41 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.72LOEUF

pLI 0.353

Z-score 2.12

OE 0.23 (0.09–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.82Z-score

OE missense 0.25 (0.18–0.34)

28 obs / 112.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.23 (0.09–0.72)

0≤0.351.4

Missense OE?0.25 (0.18–0.34)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 2 / 8.8Missense obs/exp: 28 / 112.2Syn Z: 1.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateARF3-related neurodevelopmental disorderDNAD

This gene — mechanism propensity

0.75top 25%

GOF

0.5465th %ile

LOF

0.4233th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

41 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic6

VUS17

Benign2

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	6	0	0	6
VUS	0	17	0	0	17
Likely Benign	0	0	0	0	0
Benign	0	0	1	1	2
Conflicting	—				1
Total	0	27	1	1	30

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap ARF3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →