ACAP1

Chr 17

ArfGAP with coiled-coil, ankyrin repeat and PH domains 1

Also known as: CENTB1

NCBI Gene: 9744 ENSG00000072818 UniProt: Q15027 OMIM: 607763

ACAP1 encodes a GTPase-activating protein that regulates ARF6 and is required for clathrin-dependent protein transport from recycling endosomes to the trans-Golgi network and cell surface, including regulation of integrin beta-1 export and cell migration. This gene is highly constrained against loss-of-function variation (LOEUF 0.42), but no definitive disease associations have been established in the provided data. The high constraint suggests potential for severe developmental consequences if pathogenic variants were to occur.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable GTPase activator activity and zinc ion binding activity. Predicted to be involved in protein transport. Located in membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.42

Clinical Summary— ACAP1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.068

Z-score 4.53

OE 0.26 (0.16–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.30Z-score

OE missense 0.69 (0.63–0.76)

311 obs / 447.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.26 (0.16–0.42)

0≤0.351.4

Missense OE?0.69 (0.63–0.76)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 11 / 43.0Missense obs/exp: 311 / 447.7Syn Z: 1.53

This gene — mechanism propensity

0.6937th %ile

GOF

0.76top 25%

LOF

0.3066th %ile

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

GOFprediction above median

DNprediction 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.