ARL6IP5

Chr 3

ARF like GTPase 6 interacting protein 5

Also known as: DERP11, GTRAP3-18, HSPC127, JWA, PRAF3, Yip6b, addicsin, hp22

NCBI Gene: 10550ENSG00000144746UniProt: O75915

The encoded protein regulates intracellular concentrations of taurine and glutamate by negatively modulating the SLC1A1/EAAC1 glutamate transporter and promoting its retention in the endoplasmic reticulum. Mutations cause autosomal recessive spastic paraplegia, affecting the nervous system with progressive lower limb spasticity and weakness.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
8
Pubs (1 yr)
11
P/LP submissions
0%
P/LP missense
1.25
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— ARL6IP5
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.10) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
11 unique Pathogenic / Likely Pathogenic· 30 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
1.25LOEUF
pLI 0.104
Z-score 1.23
OE 0.40 (0.16–1.25)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.37Z-score
OE missense 0.90 (0.77–1.06)
104 obs / 115.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.40 (0.16–1.25)
0≤0.351.4
Missense OE0.90 (0.77–1.06)
0≤0.61.4
Synonymous OE0.96
0≤1.21.6
LoF obs/exp: 2 / 5.0Missense obs/exp: 104 / 115.3Syn Z: 0.19
DN
0.77top 25%
GOF
0.72top 25%
LOF
0.2775th %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

Pathogenic10
Likely Pathogenic1
VUS30
Likely Benign2
10
Pathogenic
1
Likely Pathogenic
30
VUS
2
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
10
0
10
Likely Pathogenic
0
0
1
0
1
VUS
0
28
2
0
30
Likely Benign
0
2
0
0
2
Benign
0
0
0
0
0
Total03013043

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

View in ClinVar →

Protein Context — Lollipop Plot

ARL6IP5 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
ARL6IP5 reduces cisplatin-resistance by suppressing DNA repair and promoting apoptosis pathways in ovarian carcinoma
Kim JY et al.·Cell Death Dis
2022
DNA methylation in peripheral blood is associated with renal aging and renal function decline: a national community study
Yang PL et al.·Clin Epigenetics
2024
Palmitoylated small GTPase ARL15 is translocated within Golgi network during adipogenesis
Wu Y et al.·Biol Open
2021
Correction to: Deficiency of osteoblastic Arl6ip5 impaired osteoblast differentiation and enhanced osteoclastogenesis via disturbance of ER calcium homeostasis and induction of ER stress-mediated apoptosis
Wu Y et al.·Cell Death Dis
2024
Differential genomic signatures of homozygosity and a haplotype sharing Extents across breeds associated with body size variation in Korean indigenous goats.
Kim S et al.·Gene
2026
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
ADP ribosylation factor-like GTPase 6-interacting protein 5 (Arl6IP5) is an ER membrane-shaping protein that modulates ER-phagy.
Yamamoto Y et al.·J Biol Chem
2025
Literature-Guided 6-Gene Signature for the Stratification of High-Risk Acute Myeloid Leukemia.
Song JK et al.·Cancer Res Treat
2025
Identification of clinical characteristics biomarkers for rheumatoid arthritis through targeted DNA methylation sequencing.
Zhao J et al.·Int Immunopharmacol
2024
Whole exome sequencing of ENU-induced thrombosis modifier mutations in the mouse.
Tomberg K et al.·PLoS Genet
2018Functional
Prediction of the Prognosis and Treatment Responses Based on the Characteristics of Disulfidptosis-Related Genes in Patients with Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma.
Kang M et al.·Endocr Metab Immune Disord Drug Targets
2026Cohort
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients