AP4S1

Chr 14AR

adaptor related protein complex 4 subunit sigma 1

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

NCBI Gene: 11154ENSG00000100478UniProt: Q9Y587

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]

Primary Disease Associations & Inheritance

Spastic paraplegia 52, autosomal recessiveMIM #614067
AR
219
ClinVar variants
50
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— AP4S1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
50 Pathogenic / Likely Pathogenic· 74 VUS of 219 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
1.63LOEUF
pLI 0.000
Z-score 0.12
OE 0.96 (0.58–1.63)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?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.
-0.01Z-score
OE missense 1.00 (0.84–1.20)
85 obs / 84.7 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.0.96 (0.58–1.63)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.84–1.20)
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.1.09
0≤1.21.6
LoF obs/exp: 9 / 9.4Missense obs/exp: 85 / 84.7Syn Z: -0.39

ClinVar Variant Classifications

219 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic13
VUS74
Likely Benign54
Benign20
Conflicting4
37
Pathogenic
13
Likely Pathogenic
74
VUS
54
Likely Benign
20
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
0
30
0
37
Likely Pathogenic
9
2
2
0
13
VUS
1
62
11
0
74
Likely Benign
0
3
30
21
54
Benign
0
1
19
0
20
Conflicting
—4
Total17689221202

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

View in 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.

Gene2Phenotype Curations

AP4S1-related cerebral palsy spastic quadriplegic

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spastic paraplegia 52, autosomal recessive

MIM #614067

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
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
[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
Heterozygous variants in AP4S1 are not associated with a neurological phenotype.
Quiroz V et al.·Ann Clin Transl Neurol
2025
Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia.
McCullough CG et al.·Hum Mutat
2020Case report
Yield of Whole Exome Sequencing in Children With Cryptogenic Cerebral Palsy.
Sardesai AV et al.·Pediatr Neurol
2025
Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly.
Hardies K et al.·Hum Mol Genet
2015
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
Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4-Related Hereditary Spastic Paraplegia.
Alecu JE et al.·Mov Disord
2023
A Rare Homozygous AP4S1 Variant in Rwandan Siblings with Autosomal Recessive Hereditary Spastic Paraplegia Type 52 (SPG52).
Niyoyita S et al.·Genes (Basel)
2025Case report
Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families.
Tessa A et al.·Eur J Neurol
2016
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
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)

External Resources

Links to major genomics databases and tools