AP2S1

Chr 19AD

adaptor related protein complex 2 subunit sigma 1

Also known as: AP17, CLAPS2, FBH3, FBHOk, HHC3

NCBI Gene: 1175 ENSG00000042753 UniProt: P53680 OMIM: 602242

The AP2S1 protein is a component of the adaptor protein complex 2 (AP-2) that functions in clathrin-dependent endocytosis, selectively sorting membrane proteins and forming clathrin-coated vesicles for transport to early endosomes. Mutations cause hypocalciuric hypercalcemia type III, an autosomal dominant disorder affecting calcium homeostasis. The gene shows high constraint against loss-of-function variants (LOEUF 0.502), indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

One of two major clathrin-associated adaptor complexes, AP-2, is a heterotetramer which is associated with the plasma membrane. This complex is composed of two large chains, a medium chain, and a small chain. This gene encodes the small chain of this complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.501 OMIM phenotype

Clinical Summary— AP2S1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.79) — some intolerance to loss-of-function variants.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

pLI 0.785

Z-score 2.55

OE 0.11 (0.04–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.86Z-score

OE missense 0.16 (0.11–0.25)

15 obs / 92.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.11 (0.04–0.50)

0≤0.351.4

Missense OE?0.16 (0.11–0.25)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 1 / 9.4Missense obs/exp: 15 / 92.4Syn Z: 0.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateAP2S1-related developmental disorderOTHERAD

This gene — mechanism propensity

0.5575th %ile

GOF

0.5366th %ile

LOF

0.4627th %ile

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports gain-of-function as the primary mechanism.

GOF1 literature citation

Literature Evidence

GOFLoss-of-function mutations of adaptor protein-2 sigma subunit (AP2o 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3.1

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

References