ARL6IP5

Chr 3

ARF like GTPase 6 interacting protein 5

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

NCBI Gene: 10550 ENSG00000144746 UniProt: 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.

ResearchSummary from RefSeq, UniProt

Expression of this gene is affected by vitamin A. The encoded protein of this gene may be associated with the cytoskeleton. A similar protein in rats may play a role in the regulation of cell differentiation. The rat protein binds and inhibits the cell membrane glutamate transporter EAAC1. The expression of the rat gene is upregulated by retinoic acid, which results in a specific reduction in EAAC1-mediated glutamate transport. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.25

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.40 (0.16–1.25)

0≤0.351.4

Missense OE?0.90 (0.77–1.06)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 2 / 5.0Missense obs/exp: 104 / 115.3Syn Z: 0.19

Background carrier burden — how many people carry a rare variant somewhere in ARL6IP5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 250

247 rare PASS variants

Rare truncating (LoF)

1 in 980

35 rare PASS variants

Rare synonymous (reference)

1 in 340

102 rare PASS variants

Rare missense and truncating variants are carried at similar rates in ARL6IP5; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 290	1 in 2,300
South Asian	~43k	1 in 150	1 in 2,900
Remaining (unassigned)	~30k	1 in 200	1 in 570
European (Finnish)	~27k	1 in 450	1 in 2,400
Admixed American	~22k	1 in 270	1 in 750
African / African American	~21k	1 in 250	1 in 3,300
East Asian	~20k	1 in 240	1 in 2,200
Ashkenazi Jewish	~13k	≈ 1 in 6,500	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 220	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓