AP5Z1

Chr 7AR

adaptor related protein complex 5 subunit zeta 1

NCBI Gene: 9907ENSG00000242802UniProt: O43299

As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport. According to PubMed:20613862 it is a putative helicase required for efficient homologous recombination DNA double-strand break repair

Primary Disease Associations & Inheritance

Spastic paraplegia 48, autosomal recessiveMIM #613647
AR
383
ClinVar variants
39
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— AP5Z1
🧬
Gene-Disease Validity (ClinGen)
hereditary spastic paraplegia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
39 Pathogenic / Likely Pathogenic· 210 VUS of 383 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.
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?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.
-2.97Z-score
OE missense 1.37 (1.29–1.46)
700 obs / 511.2 exp
Tolerant

Tolerant to missense variation

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.1.14 (0.89–1.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.37 (1.29–1.46)
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.1.61
0≤1.21.6
LoF obs/exp: 43 / 37.7Missense obs/exp: 700 / 511.2Syn Z: -7.62

ClinVar Variant Classifications

383 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic25
VUS210
Likely Benign127
Benign4
Conflicting3
14
Pathogenic
25
Likely Pathogenic
210
VUS
127
Likely Benign
4
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
0
6
0
14
Likely Pathogenic
17
2
5
1
25
VUS
5
186
17
2
210
Likely Benign
0
1
47
79
127
Benign
0
0
2
2
4
Conflicting
—3
Total301897784383

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

View in ClinVar →

Protein Context — Lollipop Plot

AP5Z1 · 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 48, autosomal recessive

MIM #613647

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — AP5Z1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Early Diagnosis of AP5Z1/SPG48 Spastic Paraplegia: Case Report and Review of the Literature.
Papoff FMA et al.·Neuropediatrics
2024Review
AP5Z1 affects hepatocellular carcinoma growth and autophagy by regulating PTEN ubiquitination and modulating the PI3K/Akt/mTOR pathway.
Quan Z et al.·J Transl Med
2025
[A case of spastic paraplegia 48 with a novel mutation in the AP5Z1 gene].
Maruta K et al.·Rinsho Shinkeigaku
2020Review
Whole-exome sequencing to identify novel mutations of nevoid basal cell carcinoma syndrome in a Chinese population.
Lu N et al.·Cancer Biomark
2017Case report
Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48.
Pensato V et al.·Brain
2014
Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval.
Hirst J et al.·PLoS Biol
2018
Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease.
Hirst J et al.·Hum Mol Genet
2015
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