AP4S1

Chr 14AR

adaptor related protein complex 4 subunit sigma 1

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

NCBI Gene: 11154ENSG00000100478UniProt: Q9Y587OMIM: 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.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismARLOEUF 1.631 OMIM phenotype
Clinical Summary— AP4S1
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Gene-Disease Validity (ClinGen)
AP-4 deficiency syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

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 OE0.96 (0.58–1.63)
0≤0.351.4
Missense OE1.00 (0.84–1.20)
0≤0.61.4
Synonymous OE1.09
0≤1.21.6
LoF obs/exp: 9 / 9.4Missense obs/exp: 85 / 84.7Syn Z: -0.39
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongAP4S1-related cerebral palsy spastic quadriplegicLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.7229th %ile
GOF
0.6442th %ile
LOF
0.2385th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
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
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
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 full-text resultsSearch PubTator3 ↗
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