AP5Z1

Chr 7AR

adaptor related protein complex 5 subunit zeta 1

Also known as: KIAA0415, SPG48, zeta

NCBI Gene: 9907 ENSG00000242802 UniProt: O43299 OMIM: 613653

The protein functions as a putative helicase required for homologous recombination DNA double-strand break repair and may also be involved in endosomal transport as part of the AP-5 adaptor protein complex. Mutations cause spastic paraplegia 48, an autosomal recessive disorder affecting the motor system. The gene shows tolerance to loss-of-function variants (LOEUF 1.47), suggesting that complete loss of function may be required for disease manifestation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene was identified by genome-wide screen for genes involved in homologous recombination DNA double-strand break repair (HR-DSBR). The encoded protein was found in a complex with other proteins that have a role in HR-DSBR. Knockdown of this gene reduced homologous recombination, and mutations in this gene were found in patients with spastic paraplegia. It was concluded that this gene likely encodes a helicase (PMID:20613862). [provided by RefSeq, Jan 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spastic paraplegia 48, autosomal recessiveMIM #613647

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hereditary spastic paraplegia · AR · ClinGen 2022

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.47

LOEUF

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Mechanism

📖

GeneReview available — AP5Z1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.47LOEUF

pLI 0.000

Z-score -0.79

OE 1.14 (0.89–1.47)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.97Z-score

OE missense 1.37 (1.29–1.46)

700 obs / 511.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.14 (0.89–1.47)

0≤0.351.4

Missense OE?1.37 (1.29–1.46)

0≤0.61.4

Synonymous OE?1.61

0≤1.21.6

LoF obs/exp: 43 / 37.7Missense obs/exp: 700 / 511.2Syn Z: -7.62

Background carrier burden — how many people carry a rare variant somewhere in AP5Z1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 27

1,726 rare PASS variants

Rare truncating (LoF)

1 in 320

304 rare PASS variants

Rare synonymous (reference)

1 in 35

705 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AP5Z1. 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 34	1 in 320
South Asian	~43k	1 in 21	1 in 290
Remaining (unassigned)	~30k	1 in 20	1 in 350
European (Finnish)	~27k	1 in 84	1 in 730
Admixed American	~22k	1 in 25	1 in 660
African / African American	~21k	1 in 21	1 in 230
East Asian	~20k	1 in 23	1 in 380
Ashkenazi Jewish	~13k	1 in 89	1 in 480
Middle Eastern	~2,884	1 in 22	1 in 310

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 17 coding exons well covered in gnomAD exomes and genomes.? see exons ↓