ARL6IP1

protein-coding

ADP ribosylation factor like GTPase 6 interacting protein 1

Gene summary

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]

Previous symbols:

ARL6IP

MANE transcript

NM_015161.3

Inheritance

ClinVar variants

P:9U:37B:20

Top phenotype

Spastic paraplegia, autosomal recessive 61

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr16:18,791,609-18,801,572

External References & Databases

Ensembl (ENSG00000170540)

Transcript & Mutation Effects

hg38 • Region Span ~10.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 61STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014304

Submitter: PanelApp Australia

hereditary spastic paraplegia 61SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014304

Submitter: Orphanet

hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: ClinGen

*ARL6IP1* was first reported in relation to autosomal recessive hereditary spastic paraplegia (HSP) in 2014 (Novarino G et al., PMID: 24482476). This disease is caused by biallelic variation in the *ARL6IP1* gene. Phenotypes involve the nervous system and the skeletal system including spasticity, scissors gait, spasticity, and polyneuropathy. More variable features may include acropathy, absent achilles tendon reflex and increased patellar reflex. Around 2 unique frameshift variants have been reported in at least 4 probands in various publications (PMID: 24482476, 2847135, 30237576, 31272422). A loss-of-function frameshift variant was also found to segregate with the disorder in additional family members with a LOD score of 3.5 (PMID: 24482476). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by showing that a knockdown of the zebrafish *ARL6IP1* ortholog causes defects in the body axis, motor neuron morphology, and spontaneous swimming behavior (PMID: 24482476). In summary, there is definitive evidence to support the relationship of the *ARL6IP1* gene with hereditary spastic paraplegia (HSP). This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 10/17/2022 (SOP Version 9).

hereditary spastic paraplegia 61STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014304

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spastic paraplegia, autosomal recessive 61AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24482476

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARL6IP1 variants in ClinVar

5 Conditions Cataloged

Hereditary spastic paraplegia 61Total: 60

Inborn genetic diseasesTotal: 24

not providedTotal: 8

ARL6IP1-related disorderTotal: 7

not specifiedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015161.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	16 clinvar	1 clinvar	19
missense	1 clinvar		35 clinvar	2 clinvar	1 clinvar	39
nonsense	2 clinvar					2
start loss						0
frameshift	1 clinvar	3 clinvar				4
splice donor/acceptor (+/-2bp)		2 clinvar				2
Total	4	5	37	18	2	66

Highest pathogenic variant AF is 0.0000111564395

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015161.3	RefSeq	NP_055976.1	6	MANE Select
ENST00000304414.12	Ensembl	ENSP00000306788.7	6	MANE Select
NM_001313858.1	RefSeq	NP_001300787.1	5	Standard
ENST00000546206.6	Ensembl	ENSP00000440048.2	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
arl6ip1	Danio rerio	Structure: iridophore Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

arl6ip1

Danio rerio

Structure: iridophore

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of L-glutamate import across plasma membrane
cotranslational protein targeting to membrane
apoptotic process
negative regulation of apoptotic process
negative regulation of cysteine-type endopeptidase activity involved in apoptotic process

Molecular Function

protein binding
identical protein binding

Cellular Component

Sec61 translocon complex
endoplasmic reticulum membrane
cytosol
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304414
Coding exons: 6
Length: 10010
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125745
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.07	79	111	0.713	0.00000572	1313
Missense (PolyPhen)		12	17.981	0.66736		257
Synonymous	-0.722	45	39.2	1.15	0.00000210	391
Loss of Function	2.15	5	13.5	0.369	7.30e-7	135

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000062	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Positively regulates SLC1A1/EAAC1-mediated glutamate transport by increasing its affinity for glutamate in a PKC activity-dependent manner. Promotes the catalytic efficiency of SLC1A1/EAAC1 probably by reducing its interaction with ARL6IP5, a negative regulator of SLC1A1/EAAC1-mediated glutamate transport (By similarity). Plays a role in the formation and stabilization of endoplasmic reticulum tubules (PubMed:24262037). Negatively regulates apoptosis, possibly by modulating the activity of caspase-9 (CASP9). Inhibits cleavage of CASP9-dependent substrates and downstream markers of apoptosis but not CASP9 itself (PubMed:12754298). May be involved in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation (PubMed:10995579). {ECO:0000250|UniProtKB:Q9JKW0, ECO:0000269|PubMed:12754298, ECO:0000269|PubMed:24262037, ECO:0000303|PubMed:10995579}.;
Disease: DISEASE: Spastic paraplegia 61, autosomal recessive (SPG61) [MIM:615685]: A complicated form of spastic paraplegia with polysensory and motor neuropathy. Spastic paraplegia is a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:24482476}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.633
RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.955