ARFRP1

Chr 20

ARF related protein 1

Also known as: ARL18, ARP, Arp1

NCBI Gene: 10139 ENSG00000101246 UniProt: Q13795 OMIM: 604699

The protein is a trans-Golgi-associated GTPase that regulates protein sorting and controls targeting of ARL1 and its effector to the trans-Golgi, and is required for lipidation of chylomicrons in the intestine and VLDL in the liver. Mutations cause autosomal recessive perioral dermatitis with intestinal lipodystrophy. The gene shows moderate constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a membrane-associated GTP-ase which localizes to the plasma membrane and is related to the ADP-ribosylation factor (ARF) and ARF-like (ARL) proteins. This gene plays a role in membrane trafficking between the trans-Golgi network and endosomes. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, May 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.64

Clinical Summary— ARFRP1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

35 VUS of 48 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?

0.64LOEUF

pLI 0.137

Z-score 2.52

OE 0.28 (0.14–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.85Z-score

OE missense 0.79 (0.67–0.93)

103 obs / 130.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.28 (0.14–0.64)

0≤0.351.4

Missense OE?0.79 (0.67–0.93)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 4 / 14.3Missense obs/exp: 103 / 130.4Syn Z: -0.95

This gene — mechanism propensity

0.76top 25%

GOF

0.7029th %ile

LOF

0.2971th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

48 submitted variants in ClinVar

ClinVar

Classification Summary

VUS35

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	33	2	0	35
Likely Benign	1	0	0	1
Benign	0	0	1	1
Total	34	2	1	37

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

View in ClinVar →

41 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap ARFRP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →