AP1S1

Chr 7AR

adaptor related protein complex 1 subunit sigma 1

Also known as: AP19, CLAPS1, EKV3, MEDNIK, SIGMA1A

NCBI Gene: 1174ENSG00000106367UniProt: P61966

The protein encoded by this gene is part of the clathrin coat assembly complex which links clathrin to receptors in coated vesicles. These vesicles are involved in endocytosis and Golgi processing. This protein, as well as beta-prime-adaptin, gamma-adaptin, and the medium (mu) chain AP47, form the AP-1 assembly protein complex located at the Golgi vesicle. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

MEDNIK syndromeMIM #609313
AR
189
ClinVar variants
30
Pathogenic / LP
0.10
pLI score
0
Active trials
Clinical Summary— AP1S1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
30 Pathogenic / Likely Pathogenic· 26 VUS of 189 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.
0.86LOEUF
pLI 0.100
Z-score 1.85
OE 0.33 (0.15–0.86)
Tolerant

Typical tolerance to LoF variation

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.
1.74Z-score
OE missense 0.47 (0.37–0.61)
41 obs / 86.7 exp
Tolerant

Mild missense constraint

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.0.33 (0.15–0.86)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.47 (0.37–0.61)
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.0.92
0≤1.21.6
LoF obs/exp: 3 / 9.0Missense obs/exp: 41 / 86.7Syn Z: 0.40

ClinVar Variant Classifications

189 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic8
VUS26
Likely Benign104
Benign22
Conflicting2
22
Pathogenic
8
Likely Pathogenic
26
VUS
104
Likely Benign
22
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
21
0
22
Likely Pathogenic
4
0
4
0
8
VUS
1
19
6
0
26
Likely Benign
0
0
56
48
104
Benign
0
0
17
5
22
Conflicting
—2
Total61910453184

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

View in ClinVar →

Protein Context — Lollipop Plot

AP1S1 · 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

MEDNIK syndrome

MIM #609313

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion.
Rackova M et al.·J Mol Med (Berl)
2024Case report
MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features.
Incecik F et al.·Metab Brain Dis
2018Review
AP1S1 defect causing MEDNIK syndrome: a new adaptinopathy associated with defective copper metabolism.
Martinelli D et al.·Ann N Y Acad Sci
2014
Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant.
Lu JG et al.·Pediatr Dev Pathol
2023Case report
MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.
Martinelli D et al.·Brain
2013Case report
Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord.
Montpetit A et al.·PLoS Genet
2008
A Pilot Study: Contrasting Genomic Profiles of Lung Adenocarcinoma Between Patients of European and Latin American Ancestry.
Rueda-Zarazua B et al.·Int J Mol Sci
2025Cohort
Homozygous Loss-of-Function Mutations in AP1B1, Encoding Beta-1 Subunit of Adaptor-Related Protein Complex 1, Cause MEDNIK-like Syndrome.
Alsaif HS et al.·Am J Hum Genet
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Mechanism of Non-Small Cell Lung Cancer-Derived Extracellular Vesicle miRNA hsa-let-7b-5p Targeting AP1S1 to Regulate M2 Macrophage Polarization.
Liu L et al.·Int J Genomics
2026🔓 Open AccessFunctional
Feeding-Triggered Seizures in a Newborn with AP1S1-Related MEDNIK Syndrome: Expanding the Phenotype of a Hyper-Rare Disease.
Cavalli A et al.·J Clin Med
2025🔓 Open Access
IDEDNIK syndrome: a newly recognized rare genetic disorder caused by AP1S1 and AP1B1 mutations.
Wu R et al.·Front Neurol
2025🔓 Open Access
Ap1s1 reduction in the aging brain heightens neuronal vulnerability to amyloid-β and oxidative stress in Alzheimer's pathogenesis.
Yang X et al.·Alzheimers Res Ther
2025🔓 Open Access
Clinical and Genetic Functional Validation of a Novel AP1S1 Mutation Causing MEDNIK Syndrome.
Duan L et al.·Int J Genomics
2025🔓 Open AccessFunctional
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