AP1S1

Chr 7AR

adaptor related protein complex 1 subunit sigma 1

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

NCBI Gene: 1174 ENSG00000106367 UniProt: P61966 OMIM: 603531

The AP1S1 protein is a subunit of the clathrin-associated adaptor protein complex 1 that mediates protein sorting in the late-Golgi/trans-Golgi network and endosomes by recruiting clathrin to membranes and recognizing sorting signals in transmembrane cargo molecules. Mutations cause MEDNIK syndrome, a multisystem disorder affecting mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratoderma. This condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.861 OMIM phenotype

Clinical Summary— AP1S1

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Gene-Disease Validity (ClinGen)

MEDNIK syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 20 VUS of 162 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — AP1S1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.100

Z-score 1.85

OE 0.33 (0.15–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.74Z-score

OE missense 0.47 (0.37–0.61)

41 obs / 86.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.15–0.86)

0≤0.351.4

Missense OE?0.47 (0.37–0.61)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 3 / 9.0Missense obs/exp: 41 / 86.7Syn Z: 0.40

This gene — mechanism propensity

0.74top 25%

GOF

0.6638th %ile

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

162 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic6

VUS20

Likely Benign104

Benign21

Conflicting2

Pathogenic

Likely Pathogenic

VUS

104

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	1	0	4
Likely Pathogenic	6	0	0	0	6
VUS	1	19	0	0	20
Likely Benign	0	0	56	48	104
Benign	0	0	16	5	21
Conflicting	—				2
Total	10	19	73	53	157

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap AP1S1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →