ARL6IP1

Chr 16AR

ARL6 interacting reticulophagy regulator 1

Also known as: AIP1, ARL6IP, ARMER, SPG61

NCBI Gene: 23204ENSG00000170540UniProt: Q15041

This gene belongs to the ARL6ip family and encodes a transmembrane protein that is predominantly localized to intracytoplasmic membranes. It is highly expressed in early myeloid progenitor cells and thought to be involved in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation. Mutations in this gene are associated with spastic paraplegia 61 (SPG61). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2015]

Primary Disease Associations & Inheritance

Spastic paraplegia 61, autosomal recessiveMIM #615685
AR
126
ClinVar variants
20
Pathogenic / LP
0.02
pLI score
0
Active trials
Clinical Summary— ARL6IP1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 43 VUS of 126 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.78LOEUF
pLI 0.022
Z-score 2.15
OE 0.37 (0.19–0.78)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.07Z-score
OE missense 0.71 (0.59–0.86)
79 obs / 110.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.19–0.78)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.59–0.86)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.15
0≤1.21.6
LoF obs/exp: 5 / 13.5Missense obs/exp: 79 / 110.7Syn Z: -0.72

ClinVar Variant Classifications

126 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic2
VUS43
Likely Benign34
Benign23
Conflicting1
18
Pathogenic
2
Likely Pathogenic
43
VUS
34
Likely Benign
23
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
16
0
18
Likely Pathogenic
2
0
0
0
2
VUS
0
34
8
1
43
Likely Benign
0
1
19
14
34
Benign
0
1
20
2
23
Conflicting
—1
Total3376317121

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

View in ClinVar →

Protein Context — Lollipop Plot

ARL6IP1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spastic paraplegia 61, autosomal recessive

MIM #615685

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autozygome and high throughput confirmation of disease genes candidacy.
Maddirevula S et al.·Genet Med
2019
Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.
Wakil SM et al.·BMC Med Genet
2019
RNA Therapy for Oncogenic NRAS-Driven Nevi Induces Apoptosis.
Bryant D et al.·J Invest Dermatol
2025
ER-shaping proteins are required for ER and mitochondrial network organization in motor neurons.
Fowler PC et al.·Hum Mol Genet
2016
ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.
Nizon M et al.·Clin Genet
2018Case report
The inositol 5-phosphatase INPP5K participates in the fine control of ER organization.
Dong R et al.·J Cell Biol
2018
ARL6IP1 mediates cisplatin-induced apoptosis in CaSki cervical cancer cells.
Guo F et al.·Oncol Rep
2010
Genotype-phenotype study and expansion of ARL6IP1-related complicated hereditary spastic paraplegia.
Cao Y et al.·Clin Genet
2021Case report
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
Neurogenic arthrogryposis, hypotonia, dysmorphic features plus malformation of cortical development further expands the ARL6IP1 loss-of-function phenotype.
Haliloğlu G et al.·Neuromuscul Disord
2025Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools