APC2

Summary

APC2 (APC regulator of Wnt signaling pathway 2, HGNC:24036) is a protein-coding gene on chromosome 19p13.3, encoding Adenomatous polyposis coli protein 2 (O95996). Stabilizes microtubules and may regulate actin fiber dynamics through the activation of Rho family GTPases.

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.

Source: NCBI Gene 10297 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lissencephaly spectrum disorders (Strong, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 1,228 total — 14 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 137
• MANE Select transcript: NM_005883

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24036
Approved symbol	APC2
Name	APC regulator of Wnt signaling pathway 2
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	APCL
Ensembl gene	ENSG00000115266
Ensembl biotype	protein_coding
OMIM	612034
Entrez	10297

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000233607, ENST00000238483, ENST00000535453, ENST00000587149, ENST00000587869, ENST00000590469, ENST00000590877, ENST00000593146

RefSeq mRNA: 2 — MANE Select: NM_005883 NM_001351273, NM_005883

CCDS: CCDS12068

Canonical transcript exons

ENST00000590469 — 15 exons

Exon	Start	End
ENSE00000752922	1456853	1457243
ENSE00000752943	1455384	1455500
ENSE00000951261	1465155	1473244
ENSE00001261335	1457965	1458060
ENSE00003478377	1461037	1461153
ENSE00003508879	1452984	1453142
ENSE00003551707	1460181	1460320
ENSE00003587111	1460780	1460857
ENSE00003597524	1456306	1456404
ENSE00003613963	1461963	1462177
ENSE00003614514	1453431	1453611
ENSE00003634163	1453247	1453337
ENSE00003684172	1456076	1456153
ENSE00003688260	1455149	1455257
ENSE00003901260	1450121	1450338

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 98.12.

FANTOM5 (CAGE): breadth broad, TPM avg 4.8989 / max 293.8539, expressed in 297 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172972	3.2442	255
172973	0.8113	122
172969	0.6625	156
172971	0.0785	46
172970	0.0666	40
172974	0.0357	23

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
paraflocculus	UBERON:0005351	98.12	gold quality
cortical plate	UBERON:0005343	96.55	gold quality
cerebellar vermis	UBERON:0004720	96.23	gold quality
middle frontal gyrus	UBERON:0002702	95.93	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.25	gold quality
inferior olivary complex	UBERON:0002127	95.17	gold quality
ganglionic eminence	UBERON:0004023	94.84	gold quality
frontal pole	UBERON:0002795	94.79	gold quality
medulla oblongata	UBERON:0001896	93.41	gold quality
ventral tegmental area	UBERON:0002691	93.38	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.36	gold quality
inferior vagus X ganglion	UBERON:0005363	92.95	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.59	gold quality
right frontal lobe	UBERON:0002810	92.59	gold quality
pons	UBERON:0000988	92.24	gold quality
subthalamic nucleus	UBERON:0001906	92.21	gold quality
superior vestibular nucleus	UBERON:0007227	91.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.76	gold quality
amygdala	UBERON:0001876	91.71	gold quality
parietal lobe	UBERON:0001872	91.39	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.17	gold quality
postcentral gyrus	UBERON:0002581	91.04	gold quality
frontal lobe	UBERON:0016525	91.03	gold quality
frontal cortex	UBERON:0001870	91.02	gold quality
cerebellum	UBERON:0002037	90.99	gold quality
cingulate cortex	UBERON:0003027	90.93	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.90	gold quality
cerebellar cortex	UBERON:0002129	90.88	gold quality
anterior cingulate cortex	UBERON:0009835	90.87	gold quality
neocortex	UBERON:0001950	90.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting APC2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-10394-5P	99.65	66.83	1852

Literature-anchored findings (GeneRIF, showing 22)

• Familial adenomatous polyposis with adenomatous polyposis coli gene mutation at codon 1309 entails a risk of a more aggressive phenotype; early colectomy may be indicated in children harboring this gene mutation. (PMID:18157572)
• These data suggest that APC2 does not have to shuttle into the nucleus or localize to a particular subcellular location to regulate Wnt signaling. (PMID:22513088)
• APCL uses the 15 amino acid repeats region of APC to target beta-catenin for degradation. (PMID:23840886)
• We report that APC-2 gene is hypermethylated in both RB tumor samples and Y79 cells. Reduced APC-2 lead to increased Wnt signaling pathway protein, beta-catenin suggesting tumor suppressive role of APC-2 gene. (PMID:25207834)
• miR-939 functioned as a potential tumor promoter by regulating the Wnt/beta-catenin signal pathway through direct suppression of APC2 expression. (PMID:25960217)
• Data show that poly(ADP-ribose) polymerase (PARP) enzyme Tankyrase (TNKS) inhibition in colon cancer cells decreases beta-catenin signaling at the level of both Axin and APC2. (PMID:27068743)
• Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium (PMID:27694902)
• double knockdown of APC2 and miR-4326 promoted lung cancer cell proliferation, confirming that miR-4326 promoted lung cancer cell proliferation by inhibiting APC2. (PMID:29101731)
• APC2 3’-UTR is targeted by hsa-miR-11181. (PMID:29111205)
• We have also identified a functionally important SUMO interacting motif in the cullin-homology domain of APC2 located near the APC4 sumoylation sites and APC/C catalytic core. Our findings provide evidence of an important regulatory role for SUMO modification and binding in affecting APC/C activation and mitotic exit. (PMID:29517484)
• It has been found that APC2 localizes as distinct clusters along microtubule bundles in dendrites, and that this localization is driven by LC8-binding and two separate microtubule-interacting domains. (PMID:30018294)
• Results report that APC2 was hypermethylated in colorectal cancer (CRC) tissues and cell lines. An inverse correlation was observed between the APC2 methylation and its transcriptional levels. Furthermore, APC2_CPG_14 was an independent risk factor for overall survival in CRC patients. This study indicates that APC2 is hypermethylated and may be a tumorigenesis biomarker for Chinese CRC patients. (PMID:30510602)
• Hsa_circ_0009361 acted as a tumor suppressive sponge of miR-582, which could up-regulate the expression of APC2, inhibit the Wnt/beta-catenin signaling, and suppress the growth and metastasis of colorectal cancer (PMID:31109967)
• miR-3648 Promotes Prostate Cancer Cell Proliferation by Inhibiting Adenomatous Polyposis Coli 2. (PMID:31196256)
• These results demonstrate that the circ-PKD2/miR-204-3p/APC2 axis represents a novel pathway involved in the pathogenesis of oral squamous cell carcinoma (OSCC) and may serve as a novel therapeutic target of OSCC. (PMID:31206208)
• findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly (PMID:31585108)
• Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late. (PMID:32725632)
• METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding. (PMID:34155197)
• What are the roles of global DNA and APC 2 gene promotor hypermethylation in multiple myeloma? (PMID:34637096)
• High miR-3648 expression and low APC2 expression are associated with shorter survival and tumor progression in NSCLC. (PMID:34927228)
• Recessive APC2 missense variants associated with epilepsies without neurodevelopmental disorders. (PMID:37657306)
• Reprint of: Recessive APC2 missense variants associated with epilepsies without neurodevelopmental disorders. (PMID:38523034)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	apc2	ENSDARG00000063007
mus_musculus	Apc2	ENSMUSG00000020135
rattus_norvegicus	Apc2	ENSRNOG00000033791
drosophila_melanogaster	Apc	FBGN0015589
drosophila_melanogaster	Apc2	FBGN0026598
caenorhabditis_elegans	apr-1	WBGENE00000156

Paralogs (1): APC (ENSG00000134982)

Protein

Protein identifiers

Adenomatous polyposis coli protein 2 — O95996 (reviewed: O95996)

Alternative names: Adenomatous polyposis coli protein-like

All UniProt accessions (6): A0A0C4DGQ0, B5MDS5, O95996, K7ELQ3, K7EN62, K7ERC5

UniProt curated annotations — full annotation on UniProt →

Function. Stabilizes microtubules and may regulate actin fiber dynamics through the activation of Rho family GTPases. May also function in Wnt signaling by promoting the rapid degradation of CTNNB1.

Subunit / interactions. Interacts with PSRC1. Interacts with APC. Interacts with CTNNB1. Interacts with MAPRE1 and MAPRE3. Interacts with TP53BP. Interacts possibly with AXIN2.

Subcellular location. Cytoplasm. Cytoskeleton. Golgi apparatus. Perinuclear region.

Tissue specificity. Widely expressed (at protein level). Specifically expressed in the CNS.

Disease relevance. Intellectual developmental disorder, autosomal recessive 74 (MRT74) [MIM:617169] A disorder characterized by intellectual impairment, macrocephaly, and dysmorphic features. Epilepsy with eyelid myoclonus has also been reported. The disease is caused by variants affecting the gene represented in this entry. Cortical dysplasia, complex, with other brain malformations 10 (CDCBM10) [MIM:618677] An autosomal recessive disorder of aberrant neuronal migration during brain development. CDCBM10 is clinically characterized by onset in infancy of global developmental delay, impaired intellectual development, seizures, inability to ambulate, and absent language. Brain imaging shows lissencephaly, cortical dysplasia, subcortical heterotopia, and paucity of white matter. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the adenomatous polyposis coli (APC) family.

Isoforms (3)

UniProt ID	Names	Canonical?
O95996-1	1	yes
O95996-2	2
O95996-3	3

RefSeq proteins (2): NP_001338202, NP_005874* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR009223	APC_rpt	Repeat
IPR009224	SAMP	Repeat
IPR009234	APC_basic_dom	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR026818	Apc_fam	Family
IPR026831	APC_dom	Homologous_superfamily
IPR032038	APC_N	Domain
IPR036149	APC_N_sf	Homologous_superfamily
IPR041257	APC_rep	Repeat

Pfam: PF00514, PF05923, PF05924, PF05956, PF11414, PF16629, PF16689, PF18797

UniProt features (77 total): compositionally biased region 23, region of interest 17, sequence conflict 12, repeat 11, sequence variant 7, coiled-coil region 2, modified residue 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95996-F1	48.87	0.16

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 1585, 1587

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 507 (showing top): GCM_MAP4K4, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, PEREZ_TP63_TARGETS, GOBP_ACTIVATION_OF_GTPASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, MODULE_66, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_MICROTUBULE_DEPOLYMERIZATION, MODULE_379

GO Biological Process (11): microtubule cytoskeleton organization (GO:0000226), cell fate specification (GO:0001708), negative regulation of microtubule depolymerization (GO:0007026), pattern specification process (GO:0007389), nervous system development (GO:0007399), Wnt signaling pathway (GO:0016055), cell migration (GO:0016477), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of canonical Wnt signaling pathway (GO:0090090), activation of GTPase activity (GO:0090630), negative regulation of Wnt signaling pathway (GO:0030178)

GO Molecular Function (4): beta-catenin binding (GO:0008013), microtubule binding (GO:0008017), gamma-catenin binding (GO:0045295), protein binding (GO:0005515)

GO Cellular Component (17): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), microtubule (GO:0005874), actin filament (GO:0005884), microtubule cytoskeleton (GO:0015630), catenin complex (GO:0016342), midbody (GO:0030496), beta-catenin destruction complex (GO:0030877), lamellipodium membrane (GO:0031258), intercellular bridge (GO:0045171), perinuclear region of cytoplasm (GO:0048471), cytoskeleton (GO:0005856), cytoplasmic microtubule (GO:0005881), leading edge membrane (GO:0031256), filamentous actin (GO:0031941), plasma membrane bounded cell projection (GO:0120025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	4
protein binding	2
polymeric cytoskeletal fiber	2
cytoskeleton organization	1
microtubule-based process	1
cell fate commitment	1
cellular developmental process	1
microtubule depolymerization	1
negative regulation of microtubule polymerization or depolymerization	1
regulation of microtubule depolymerization	1
negative regulation of protein depolymerization	1
negative regulation of supramolecular fiber organization	1
multicellular organism development	1
multicellular organismal process	1
system development	1
cell surface receptor signaling pathway	1
cell motility	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
positive regulation of GTPase activity	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
tubulin binding	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
microtubule cytoskeleton	1
actin cytoskeleton	1
cytoskeleton	1
extrinsic component of plasma membrane	1
plasma membrane protein complex	1
intracellular protein-containing complex	1
catalytic complex	1
lamellipodium	1

Protein interactions and networks

STRING

914 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APC2	AXIN1	O15169	895
APC2	MAPRE3	Q9UPY8	735
APC2	KHK	P50053	716
APC2	MAPRE2	Q15555	673
APC2	GSK3B	P49841	594
APC2	MAPRE1	Q15691	580
APC2	CTNNB1	P35222	573
APC2	AXIN2	Q9Y2T1	559
APC2	TCF7	P36402	545
APC2	TLDC2	A0PJX2	464
APC2	RASSF1	Q9NS23	433
APC2	LRRC24	Q50LG9	417
APC2	CDH13	P55290	399
APC2	BCLAF3	A2AJT9	370
APC2	TCFL5	Q9UL49	347

IntAct

26 interactions, top by confidence:

A	B	Type	Score
YBX1	HNRNPR	psi-mi:“MI:0914”(association)	0.770
APC2	MAPRE3	psi-mi:“MI:0915”(physical association)	0.610
APC2	MAPRE3	psi-mi:“MI:0407”(direct interaction)	0.610
MAPRE3	APC2	psi-mi:“MI:0403”(colocalization)	0.610
TP53BP2	APC2	psi-mi:“MI:0915”(physical association)	0.540
APC2	TP53BP2	psi-mi:“MI:0915”(physical association)	0.540
APC2	TP53BP2	psi-mi:“MI:0403”(colocalization)	0.540
MAPRE1	APC2	psi-mi:“MI:0915”(physical association)	0.530
MAPRE1	APC2	psi-mi:“MI:0407”(direct interaction)	0.530
APC2	MAPRE1	psi-mi:“MI:0407”(direct interaction)	0.530
YAP1	APC2	psi-mi:“MI:0407”(direct interaction)	0.440
APC2	FXR1	psi-mi:“MI:0915”(physical association)	0.370
APC2	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
APC2	SMARCA2	psi-mi:“MI:0915”(physical association)	0.370
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
TIMP2	APC2	psi-mi:“MI:0915”(physical association)	0.000
DISC1	APC2	psi-mi:“MI:0915”(physical association)	0.000
DSCAM	APC2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): TP53BP2 (Two-hybrid), APC2 (Reconstituted Complex), TP53BP2 (Co-localization), ACTA1 (Co-localization), APC2 (Affinity Capture-RNA), APC2 (Two-hybrid), APC2 (Reconstituted Complex), APC2 (Affinity Capture-MS), APC2 (Affinity Capture-MS), APC2 (Two-hybrid), APC2 (Two-hybrid), APC2 (Two-hybrid), APC2 (Reconstituted Complex), APC2 (Protein-peptide), APC2 (Negative Genetic)

ESM2 similar proteins: A2ARS0, A5PJP1, A5PKW4, A6QQ91, C9JTQ0, D3ZG83, F1MUS9, O14512, O14559, O75427, O95996, P0C0T2, P46062, Q02779, Q09019, Q12852, Q18PE0, Q18PE1, Q1LZC5, Q2KI85, Q2TAL5, Q2VPJ9, Q3UMT1, Q53LP3, Q566C8, Q5BJT1, Q5DTT2, Q60700, Q63HR2, Q66L42, Q69YU3, Q6GQX6, Q6NSJ2, Q6NXT1, Q6QNY0, Q7TN12, Q80YF9, Q86YV0, Q8C0J6, Q8C2K5

Diamond homologs: A8X633, O95996, P25054, P70478, Q21227, Q61315, Q9Z1K7, P70039

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
APC2	up-regulates	GSK3B/Axin/APC	binding
APC2	up-regulates	AXIN1	binding
APC2	“down-regulates quantity by destabilization”	CTNNB1	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

1228 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	12
Uncertain significance	707
Likely benign	410
Benign	51

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1339351	NM_005883.3(APC2):c.6620C>T (p.Pro2207Leu)	Pathogenic
1807799	GRCh37/hg19 19p13.3(chr19:1205244-1479188)x1	Pathogenic
2020496	NM_005883.3(APC2):c.1741del (p.Leu581fs)	Pathogenic
267259	NM_005883.3(APC2):c.5199dup (p.Lys1734fs)	Pathogenic
2972900	NM_005883.3(APC2):c.1694_1695del (p.Thr565fs)	Pathogenic
3242688	NC_000019.9:g.(?1461942)(1462196_?)del	Pathogenic
3689072	NM_005883.3(APC2):c.1176_1189del (p.Asp392fs)	Pathogenic
4085202	NM_005883.3(APC2):c.1000_1016dup (p.Ala340fs)	Pathogenic
4689442	NM_005883.3(APC2):c.650_656dup (p.Glu220fs)	Pathogenic
4717144	NM_005883.3(APC2):c.1395C>A (p.Tyr465Ter)	Pathogenic
694620	NM_005883.3(APC2):c.1081C>T (p.Gln361Ter)	Pathogenic
694621	NM_005883.3(APC2):c.6645del (p.Ala2217fs)	Pathogenic
694622	NM_005883.3(APC2):c.737C>A (p.Ser246Ter)	Pathogenic
694623	NM_005883.3(APC2):c.2840_2846del (p.Leu947fs)	Pathogenic
2434404	NM_005883.3(APC2):c.6638_6640delinsCT (p.Glu2213fs)	Likely pathogenic
2444065	NM_005883.3(APC2):c.3397C>T (p.Arg1133Ter)	Likely pathogenic
2444253	NM_005883.3(APC2):c.759dup (p.Glu254fs)	Likely pathogenic
3057693	NM_005883.3(APC2):c.1638+1G>C	Likely pathogenic
3255193	NM_005883.3(APC2):c.409del (p.Glu137fs)	Likely pathogenic
3337434	NM_005883.3(APC2):c.2153_2168del (p.Leu718fs)	Likely pathogenic
3347780	NM_005883.3(APC2):c.2916_2923del (p.Cys974fs)	Likely pathogenic
3377276	NM_005883.3(APC2):c.2931del (p.Glu977fs)	Likely pathogenic
3377277	NM_005883.3(APC2):c.6184_6193del (p.Pro2062fs)	Likely pathogenic
3393101	NM_005883.3(APC2):c.797dup (p.Gln267fs)	Likely pathogenic
4796569	NM_005883.3(APC2):c.935dup (p.Cys313fs)	Likely pathogenic
916556	NM_005883.3(APC2):c.665T>C (p.Ile222Thr)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:1455421:T:C	L187P	1.000
19:1456872:T:C	L279P	1.000
19:1456932:C:T	S299F	1.000
19:1458024:T:C	F423L	1.000
19:1458026:T:A	F423L	1.000
19:1458026:T:G	F423L	1.000
19:1460293:C:A	N472K	1.000
19:1460293:C:G	N472K	1.000
19:1460295:T:C	L473P	1.000
19:1460300:T:C	F475L	1.000
19:1460302:T:A	F475L	1.000
19:1460302:T:G	F475L	1.000
19:1460320:G:C	K481N	1.000
19:1460320:G:T	K481N	1.000
19:1461056:G:C	R514P	1.000
19:1461060:C:A	N515K	1.000
19:1461060:C:G	N515K	1.000
19:1461067:T:A	W518R	1.000
19:1461067:T:C	W518R	1.000
19:1461069:G:C	W518C	1.000
19:1461069:G:T	W518C	1.000
19:1461996:T:A	W558R	1.000
19:1461996:T:C	W558R	1.000
19:1461998:G:C	W558C	1.000
19:1461998:G:T	W558C	1.000
19:1461999:A:G	N559D	1.000
19:1462001:T:A	N559K	1.000
19:1462001:T:G	N559K	1.000
19:1462003:T:C	L560P	1.000
19:1462128:G:C	G602R	1.000

dbSNP variants (sampled 300 via entrez): RS1000005384 (19:1446400 G>T), RS1000062445 (19:1447775 G>A), RS1000205509 (19:1465786 G>A), RS1000270642 (19:1460390 C>G,T), RS1000447049 (19:1470594 G>C), RS1000455360 (19:1455180 GAGA>G), RS1000466101 (19:1461634 C>G,T), RS1000497588 (19:1447999 T>C), RS1000528721 (19:1456722 C>A,T), RS1000577284 (19:1465482 G>C,T), RS1000584655 (19:1452111 G>C,T), RS1000777058 (19:1453935 G>A,C), RS1000864276 (19:1470363 C>T), RS1000895564 (19:1470577 G>A), RS1000945533 (19:1473629 G>A)

Disease associations

OMIM: gene MIM:612034 | disease phenotypes: MIM:617169, MIM:618677, MIM:614039, MIM:189960

GenCC curated gene-disease

Disease	Classification	Inheritance
cortical dysplasia, complex, with other brain malformations 10	Strong	Autosomal recessive
Sotos syndrome	Supportive	Autosomal dominant
intellectual developmental disorder, autosomal recessive 74	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
lissencephaly spectrum disorders	Strong	AR

Mondo (6): intellectual developmental disorder, autosomal recessive 74 (MONDO:0014951), cortical dysplasia, complex, with other brain malformations 10 (MONDO:0032866), breast ductal adenocarcinoma (MONDO:0005590), complex cortical dysplasia with other brain malformations 1 (MONDO:0013541), esophageal atresia/tracheoesophageal fistula (MONDO:0008586), Sotos syndrome (MONDO:0019349)

Orphanet (2): Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation (Orphanet:300570), Esophageal atresia (Orphanet:1199)

HPO phenotypes

137 total (30 of 137 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000047	Hypospadias
HP:0000073	Ureteral duplication
HP:0000074	Ureteropelvic junction obstruction
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000083	Renal insufficiency
HP:0000098	Tall stature
HP:0000104	Renal agenesis
HP:0000126	Hydronephrosis
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000189	Narrow palate
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000405	Conductive hearing impairment
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D058495	Sotos Syndrome	C16.131.077.889; C16.131.260.905; C16.320.180.905
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	increases expression	1
ferrous chloride	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
CGP 52608	increases reaction, affects binding	1
CD 437	decreases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cannabinoids	increases abundance, affects methylation	1
Carmustine	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tamoxifen	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Lithium Chloride	decreases expression	1
Zinc Sulfate	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8HD	Ubigene HCT 116 APC2 KO	Cancer cell line	Male
CVCL_D9XM	Ubigene HeLa APC2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

17 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT04993235	Not specified	UNKNOWN	Body Perception and Representation in Overgrowth Syndromes, Behavioral Assessment and Neuropsychological Development
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair