AP4S1

Chr 14AR

adaptor related protein complex 4 subunit sigma 1

Also known as: AP47B, CLA20, CLAPS4, CPSQ6, SPG52

NCBI Gene: 11154 ENSG00000100478 UniProt: Q9Y587 OMIM: 607243

This protein is the small subunit of adaptor protein complex-4, which mediates vesicle formation and sorting of integral membrane proteins in the secretory and endocytic pathways at the Golgi apparatus and trans-Golgi network. Mutations cause spastic paraplegia 52 through an autosomal recessive inheritance pattern. The pathogenic mechanism appears to involve dominant-negative effects disrupting normal protein complex function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the adaptor complexes small subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spastic paraplegia 52, autosomal recessiveMIM #614067

Clinical highlights

Gene-disease validity (ClinGen)

AP-4 deficiency syndrome · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.63

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — AP4S1

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?

1.63LOEUF

pLI 0.000

Z-score 0.12

OE 0.96 (0.58–1.63)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.01Z-score

OE missense 1.00 (0.84–1.20)

85 obs / 84.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.96 (0.58–1.63)

0≤0.351.4

Missense OE?1.00 (0.84–1.20)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 9 / 9.4Missense obs/exp: 85 / 84.7Syn Z: -0.39

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

AP4S1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — AP4S1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

HSPHereditary Spastic ParaplegiaHereditary Spastic Paraparesis

Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)

NOT YET RECRUITING

NCT06948019Phase PHASE1, PHASE2BlackfinBio LtdStarted 2025-08

BFB-101 (AAV9-CBh-AP4B1)

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Ap4s1 truncation leads to axonal defects in a zebrafish model of spastic paraplegia 52.

Li Y et al.·Int J Dev Neurosci

2023Functional

Splice effect of a synonymous variant in AP4B1: multiomics approach establishes the diagnosis in two sisters with spastic paraplegia.

Badmann S et al.·Hum Mutat

2026

Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4M1-associated hereditary spastic paraplegia (SPG50).

Eberhardt K et al.·Stem Cell Res

2021

High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia

Ebrahimi-Fakhari D et al.·Brain Commun

2021Functional

Diagnostic Utility of the ATG9A Ratio in AP-4-Associated Hereditary Spastic Paraplegia.

Agianda HAP et al.·Ann Clin Transl Neurol

2026

Top 5 full-text resultsSearch PubTator3 ↗

Key Publications

Landmark & review papers · by relevance

PubMed

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Ebrahimi-Fakhari D et al.·Brain

2020

Yield of Whole Exome Sequencing in Children With Cryptogenic Cerebral Palsy.

Sardesai AV et al.·Pediatr Neurol

2025

Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4-Related Hereditary Spastic Paraplegia.

Alecu JE et al.·Mov Disord

2023

Combined generalized and focal epilepsy with reflex features in Adaptor protein complex 4-associated hereditary spastic paraplegias: A cohort observational study.

Bartolini E et al.·Seizure

2024Cohort

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort.

Zare Ashrafi F et al.·Arch Iran Med

2023Cohort

Top 5 results · since 2015Search PubMed ↗

Recent Gene-Specific Literature

Gene in title · MEDLINE · newest first

Europe PMC

[Clinical characteristics and genetic study of a child with Spastic paraplegia 52 due to variant of AP4S1 gene and a literature review].

Yang L et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi

2025Review

Hereditary Spastic Paraplegy Associated with the AP4S1 Gene: A Case Series Highlighting Diagnostic Pitfalls and Phenotypic Variability.

Günay Ç et al.·Mol Syndromol

2025Cohort

A Rare Homozygous AP4S1 Variant in Rwandan Siblings with Autosomal Recessive Hereditary Spastic Paraplegia Type 52 (SPG52).

Niyoyita S et al.·Genes (Basel)

2025Open Access

Heterozygous variants in AP4S1 are not associated with a neurological phenotype.

Quiroz V et al.·Ann Clin Transl Neurol

2025Open Access

Autosomal Dominant Spastic Paraplegia With Dysregulation of Bowel Function Associated With Heterozygous AP4S1 Gene Mutation: Case Report.

Popescu C.·Neurol Genet

2024Open AccessCase report

Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

AP4S1

Primary Disease Associations & Inheritance

Clinical highlights

Population Genetics & Constraint

ClinVar Variant Classifications

Protein Context — Lollipop Plot

Mechanism of Pathogenicity

Tissue Expression

Transcripts & Isoforms

Transcript architecture

DECIPHER · Gene2Phenotype

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

GenCC Classifications

Disease Associations

External Resources

Clinical Trials

External Resources

Mechanism of Pathogenicity

Transcripts & Isoforms