ARL6IP1

Chr 16AR

ARL6 interacting reticulophagy regulator 1

Also known as: AIP1, ARL6IP, ARMER, SPG61

NCBI Gene: 23204 ENSG00000170540 UniProt: Q15041 OMIM: 607669

The protein regulates glutamate transport by enhancing SLC1A1/EAAC1 transporter activity, forms and stabilizes endoplasmic reticulum tubules, and negatively regulates apoptosis. Mutations cause spastic paraplegia 61, an autosomal recessive disorder affecting the corticospinal tracts and leading to progressive lower limb spasticity. The gene shows relatively low constraint to loss-of-function variation (pLI 0.02, LOEUF 0.78).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.781 OMIM phenotype

Clinical Summary— ARL6IP1

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Gene-Disease Validity (ClinGen)

hereditary spastic paraplegia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 38 VUS of 108 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?

0.78LOEUF

pLI 0.022

Z-score 2.15

OE 0.37 (0.19–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.07Z-score

OE missense 0.71 (0.59–0.86)

79 obs / 110.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.19–0.78)

0≤0.351.4

Missense OE?0.71 (0.59–0.86)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 13.5Missense obs/exp: 79 / 110.7Syn Z: -0.72

This gene — mechanism propensity

0.79top 25%

GOF

0.7125th %ile

LOF

0.1796th %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

108 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic3

VUS38

Likely Benign34

Benign23

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	1	0	0	4
Likely Pathogenic	3	0	0	0	3
VUS	0	34	3	1	38
Likely Benign	0	1	19	14	34
Benign	0	1	20	2	23
Conflicting	—				1
Total	6	37	42	17	103

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap ARL6IP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →