APC2

Chr 19AR

APC regulator of Wnt signaling pathway 2

Also known as: APCL, MRT74

NCBI Gene: 10297 ENSG00000115266 UniProt: Q9UJX6 OMIM: 612034

APC2 encodes a component of the anaphase-promoting complex that regulates cell cycle progression by targeting specific proteins like mitotic cyclins for degradation through ubiquitination. Biallelic mutations cause autosomal recessive intellectual developmental disorder and complex cortical dysplasia with other brain malformations. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.23), consistent with its essential role in cell division.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a strongly conserved protein that has an N-terminal coiled-coil domain followed by an armadillo domain, five 20-amino acid repeats, and two SAMP domains. This protein promotes the assembly of a multiprotein complex that recruits and phosphorylates the Wnt effector beta-catenin and targets beta-catenin for ubiquitylation and proteasomal degradation. This protein therefore plays a role in the reduction of cytoplasmic levels of beta-catenin which in turn reduces activation of Wnt target genes that play a pivotal role in the pathogenesis of various human cancers. The protein encoded by this gene is closely related to the adenomatous polyposis coli (APC) tumor-suppressor protein and has similar tumor-suppressor effects. This gene also plays a role in actin assembly, cell-cell adhesion, and microtubule network formation through its interaction with cytoskeletal proteins. This gene has its highest expression in the central nervous system and is involved in brain development through cytoskeletal regulation in neurons. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.232 OMIM phenotypes

Clinical Summary— APC2

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Gene-Disease Validity (ClinGen)

lissencephaly spectrum disorders · ARStrong

Strong evidence — appropriate for clinical testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 6.24

OE 0.12 (0.07–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.75Z-score

OE missense 0.94 (0.89–0.98)

1015 obs / 1084.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.07–0.23)

0≤0.351.4

Missense OE?0.94 (0.89–0.98)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 7 / 58.5Missense obs/exp: 1015 / 1084.9Syn Z: -2.43

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongAPC2-related lissencephaly, subcortical heterotopia, and global developmental delayLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4189th %ile

GOF

0.5170th %ile

LOF

0.75top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.