AXIN2

Summary

AXIN2 (axin 2, HGNC:904) is a protein-coding gene on chromosome 17q24.1, encoding Axin-2 (Q9Y2T1). Inhibitor of the Wnt signaling pathway. It is haploinsufficient (ClinGen: sufficient evidence).

The Axin-related protein, Axin2, presumably plays an important role in the regulation of the stability of beta-catenin in the Wnt signaling pathway, like its rodent homologs, mouse conductin/rat axil. In mouse, conductin organizes a multiprotein complex of APC (adenomatous polyposis of the colon), beta-catenin, glycogen synthase kinase 3-beta, and conductin, which leads to the degradation of beta-catenin. Apparently, the deregulation of beta-catenin is an important event in the genesis of a number of malignancies. The AXIN2 gene has been mapped to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. Mutations in this gene have been associated with colorectal cancer with defective mismatch repair.

Source: NCBI Gene 8313 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oligodontia-cancer predisposition syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 4,361 total — 161 pathogenic, 31 likely-pathogenic (top 1% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 12 tissues, sQTL in 21 (q < 0.05)
• Phenotypes (HPO): 22
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.40 (moderately constrained)
• MANE Select transcript: NM_004655
• Interaction hub: 2,184 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:904
Approved symbol	AXIN2
Name	axin 2
Location	17q24.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC126582, DKFZp781B0869
Ensembl gene	ENSG00000168646
Ensembl biotype	protein_coding
OMIM	604025
Entrez	8313

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 15 protein_coding, 1 retained_intron

MANE Select: ENST00000307078

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 2, TSL 3: 2, TSL 5: 2

ENST00000307078, ENST00000375702, ENST00000544103, ENST00000577278, ENST00000578251, ENST00000580513, ENST00000585045, ENST00000618960, ENST00000881031, ENST00000881032, ENST00000881033, ENST00000881034, ENST00000881035, ENST00000936614, ENST00000936615, ENST00001139412

RefSeq mRNA: 2 — MANE Select: NM_004655 NM_001363813, NM_004655

CCDS: CCDS11662, CCDS86634

Canonical transcript exons

ENST00000307078 — 11 exons

Exon	Start	End
ENSE00001313720	65528563	65530102
ENSE00002208797	65537324	65537835
ENSE00002217078	65533912	65534079
ENSE00002234098	65538203	65538343
ENSE00002259548	65536320	65536553
ENSE00002314183	65536869	65537063
ENSE00003491851	65535626	65535721
ENSE00003596705	65549520	65549660
ENSE00003603935	65541455	65541557
ENSE00003798533	65557806	65558736
ENSE00003845504	65561450	65561648

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 92.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.6536 / max 457.1661, expressed in 1154 samples.

Highest expression (Bgee): oviduct epithelium, upper arm skin, body of uterus, tibialis anterior, thymus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

AXIN2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 21 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 33 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells EBV-transformed lymphocytes	eqtl	2.6e-40	+1.06	17:65564173:AAAATC:A
Muscle Skeletal	sqtl	1.1e-18	+0.49	17:65541780:T:C
Skin Sun Exposed Lower leg	sqtl	2.6e-12	+0.38	17:65545379:T:C
Whole Blood	eqtl	6.7e-11	+0.26	17:65564173:AAAATC:A
Esophagus Muscularis	sqtl	9.1e-11	+0.45	17:65536057:A:G
Thyroid	sqtl	3.0e-10	+0.42	17:65541780:T:C
Colon Transverse	sqtl	8.0e-10	+0.45	17:65545379:T:C
Testis	eqtl	3.1e-09	+0.15	17:65536796:A:G
Artery Tibial	sqtl	1.9e-08	+0.38	17:65541780:T:C
Nerve Tibial	sqtl	2.4e-08	+0.38	17:65545379:T:C
Colon Sigmoid	sqtl	2.6e-07	+0.44	17:65536649:C:G
Testis	sqtl	1.7e-06	+0.50	17:65545379:T:C
Esophagus Gastroesophageal Junction	sqtl	3.9e-06	+0.52	17:65541780:T:C
Lung	sqtl	1.0e-05	+0.29	17:65545379:T:C
Breast Mammary Tissue	sqtl	1.4e-05	+0.35	17:65541780:T:C
Skin Not Sun Exposed Suprapubic	sqtl	1.5e-05	+0.25	17:65545379:T:C
Adipose Visceral Omentum	sqtl	6.0e-05	+0.30	17:65541780:T:C
Brain Cortex	sqtl	9.6e-05	+0.56	17:65545379:T:C
Cells Cultured fibroblasts	eqtl	1.3e-04	-0.10	17:65687670:C:T
Spleen	sqtl	1.4e-04	+0.51	17:65541780:T:C

FANTOM5 promoters

9 alternative TSS:

Promoter ID	TPM avg	Samples expressed
167640	3.6421	833
167636	1.8919	419
167642	0.8297	448
167639	0.6620	352
167637	0.6179	258
167644	0.5013	178
167643	0.1781	74
167641	0.1679	78
167638	0.1628	60

Top tissues by expression

showing 100 of 245 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	92.93	gold quality
upper arm skin	UBERON:0004263	91.61	gold quality
body of uterus	UBERON:0009853	88.79	gold quality
tibialis anterior	UBERON:0001385	88.78	silver quality
thymus	UBERON:0002370	88.73	gold quality
germinal epithelium of ovary	UBERON:0001304	88.46	gold quality
right lung	UBERON:0002167	88.45	gold quality
ileal mucosa	UBERON:0000331	88.35	gold quality
fallopian tube	UBERON:0003889	87.95	gold quality
right uterine tube	UBERON:0001302	87.73	gold quality
cartilage tissue	UBERON:0002418	87.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.90	gold quality
upper leg skin	UBERON:0004262	85.70	gold quality
upper lobe of lung	UBERON:0008948	85.70	gold quality
upper lobe of left lung	UBERON:0008952	85.62	gold quality
endocervix	UBERON:0000458	85.50	gold quality
left uterine tube	UBERON:0001303	85.40	gold quality
uterus	UBERON:0000995	85.33	gold quality
lung	UBERON:0002048	85.29	gold quality
endometrium	UBERON:0001295	84.93	gold quality
parietal pleura	UBERON:0002400	84.93	gold quality
ovary	UBERON:0000992	84.83	gold quality
myometrium	UBERON:0001296	84.70	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.67	gold quality
lower esophagus	UBERON:0013473	84.63	gold quality
rectum	UBERON:0001052	84.59	gold quality
right ovary	UBERON:0002118	84.12	gold quality
right adrenal gland cortex	UBERON:0035827	84.08	gold quality
right lobe of thyroid gland	UBERON:0001119	84.06	gold quality
prostate gland	UBERON:0002367	83.79	gold quality
female reproductive system	UBERON:0000474	83.73	gold quality
gastrocnemius	UBERON:0001388	83.62	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.58	gold quality
left ovary	UBERON:0002119	83.56	gold quality
smooth muscle tissue	UBERON:0001135	83.52	gold quality
lower lobe of lung	UBERON:0008949	83.47	gold quality
right adrenal gland	UBERON:0001233	83.35	gold quality
mucosa of transverse colon	UBERON:0004991	83.35	gold quality
left lobe of thyroid gland	UBERON:0001120	83.34	gold quality
visceral pleura	UBERON:0002401	83.21	gold quality
mucosa of stomach	UBERON:0001199	83.18	gold quality
muscle of leg	UBERON:0001383	83.10	gold quality
left adrenal gland	UBERON:0001234	82.73	gold quality
left adrenal gland cortex	UBERON:0035825	82.67	gold quality
thyroid gland	UBERON:0002046	82.66	gold quality
sural nerve	UBERON:0015488	82.57	gold quality
uterine cervix	UBERON:0000002	82.39	gold quality
skin of hip	UBERON:0001554	82.39	gold quality
adrenal cortex	UBERON:0001235	82.26	gold quality
placenta	UBERON:0001987	82.25	gold quality
skin of abdomen	UBERON:0001416	81.99	gold quality
transverse colon	UBERON:0001157	81.88	gold quality
caput epididymis	UBERON:0004358	81.83	gold quality
cortical plate	UBERON:0005343	81.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.66	gold quality
colonic epithelium	UBERON:0000397	81.66	gold quality
zone of skin	UBERON:0000014	81.55	gold quality
colonic mucosa	UBERON:0000317	81.38	gold quality
adult organism	UBERON:0007023	81.36	gold quality
left ventricle myocardium	UBERON:0006566	81.34	gold quality
descending thoracic aorta	UBERON:0002345	81.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	81.26	gold quality
muscle tissue	UBERON:0002385	81.08	gold quality
adrenal gland	UBERON:0002369	81.03	gold quality
thoracic aorta	UBERON:0001515	81.01	gold quality
nasal cavity mucosa	UBERON:0001826	80.92	gold quality
ascending aorta	UBERON:0001496	80.86	gold quality
skin of leg	UBERON:0001511	80.74	gold quality
skeletal muscle tissue	UBERON:0001134	80.70	gold quality
ectocervix	UBERON:0012249	80.65	gold quality
colon	UBERON:0001155	80.59	gold quality
large intestine	UBERON:0000059	80.51	gold quality
deltoid	UBERON:0001476	80.50	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	80.30	silver quality
nipple	UBERON:0002030	79.93	gold quality
cardiac atrium	UBERON:0002081	79.81	gold quality
right atrium auricular region	UBERON:0006631	79.75	gold quality
intestine	UBERON:0000160	79.64	gold quality
fundus of stomach	UBERON:0001160	79.64	gold quality
quadriceps femoris	UBERON:0001377	79.61	silver quality
stomach	UBERON:0000945	79.50	gold quality
right frontal lobe	UBERON:0002810	79.46	gold quality
muscle layer of sigmoid colon	UBERON:0035805	79.43	gold quality
body of stomach	UBERON:0001161	79.24	gold quality
urinary bladder	UBERON:0001255	79.19	gold quality
heart left ventricle	UBERON:0002084	78.97	gold quality
primary visual cortex	UBERON:0002436	78.82	gold quality
Brodmann (1909) area 23	UBERON:0013554	78.82	silver quality
apex of heart	UBERON:0002098	78.81	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.79	silver quality
peritoneum	UBERON:0002358	78.77	gold quality
esophagus	UBERON:0001043	78.74	gold quality
omental fat pad	UBERON:0010414	78.74	gold quality
cardiac ventricle	UBERON:0002082	78.71	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.70	gold quality
pylorus	UBERON:0001166	78.66	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.64	gold quality
vagina	UBERON:0000996	78.53	gold quality
calcaneal tendon	UBERON:0003701	78.44	gold quality
bronchial epithelial cell	CL:0002328	78.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.05

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Hippocampus	tissue	26.1	medium
Choroid plexus	tissue	24.5
Postcentral gyrus	tissue	20.5
Locus coeruleus	tissue	20.0
Endometrium 1	tissue	17.7	medium
Placenta	tissue	17.3	high
Smooth muscle	tissue	16.2	medium
Thymus	tissue	16.1
Nucleus accumbens	tissue	15.8
Hippocampal formation	tissue	14.6
Skin 1	tissue	14.1	medium
Rectum	tissue	13.7	medium
Fallopian tube	tissue	13.6	low
Cerebral cortex	tissue	13.3	high
Olfactory bulb	tissue	13.3
Insular cortex	tissue	13.3
Entorhinal cortex	tissue	13.2
Lung	tissue	13.1	high
Prostate	tissue	13.1	low
Amygdala	tissue	13.0
Stomach 1	tissue	12.9	medium
Superior colliculi	tissue	12.3
Temporal cortex	tissue	12.3
Prefrontal cortex	tissue	12.2
Motor cortex	tissue	11.8
Retrosplenial and cingulate cortex	tissue	11.8
Thalamus	tissue	11.7
Retrosplenial cortex	tissue	11.7
Colon	tissue	11.6	high
Somatosensory cortex	tissue	11.4
Cervix	tissue	11.1	medium
Spinal cord	tissue	11.1
Frontal cortex	tissue	10.9
Basal ganglia	tissue	10.8	medium
Occipital cortex	tissue	10.4
Ovary	tissue	10.2	medium
Cerebellum	tissue	10.2	medium
Septum	tissue	10.1
Thyroid gland	tissue	10.0	high
Caudate putamen	tissue	9.8
Midbrain	tissue	9.6
Hypothalamus	tissue	9.5
Ventral forebrain	tissue	9.1
Skeletal muscle	tissue	9.0	high
Periaqueductal gray	tissue	9.0
Medulla oblongata	tissue	8.9
Substantia nigra	tissue	8.5
Seminal vesicle	tissue	8.4	medium
Pons	tissue	8.0
Corpus callosum	tissue	7.9
Putamen	tissue	7.7
Vagina	tissue	7.4	high
Tongue	tissue	7.3
Small intestine	tissue	7.0	high
Spleen	tissue	6.8	medium
Duodenum	tissue	6.7	high
Adrenal gland	tissue	6.6	medium
Testis	tissue	6.3	high
Gallbladder	tissue	6.2	high
Pituitary gland	tissue	5.9

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Posterior thalamic nucleus (36.7), Habenula (34.5), Ventral posteromedial thalamic nucleus (32.7), Medial dorsal thalamic nucleus (32.3), Hippocampus, CA3 (32.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APP, ASCL1, CDX2, CTNNB1, DLX4, DNMT3A, E2F1, ESR1, FHIT, GRHL3, HNF4A, MYC, NFATC4, NR4A2, RUNX2, RUNX3, SATB2, SOX17, SOX4, TCF7, TCF7L2, WNT3A

miRNA regulators (miRDB)

Targeting AXIN2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 114 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.397, missense Z -0.0129 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000307078 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
17:65,529,979–65,534,012	65 / 95.7	0.68	no
17:65,534,013–65,558,530	1053 / 973.5	1.08	no
17:65,558,531–65,558,574	3 / 21.1	0.14	yes (p 8.0e-05)
17:65,558,575–65,558,620	23 / 20.8	1.11	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Activation of AXIN2 expression by beta-catenin-T cell factor (PMID:11940574)
• Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer (PMID:15042511)
• axin2 expression is regulated by its alternative 5’UTR mRNA (PMID:15611123)
• E2F1 induces stabilisation of axin2 mRNAs (PMID:15766563)
• epigenetic silencing of AXIN2 is specifically associated with carcinogenesis in colorectal carcinoma with microsatellite instability (PMID:16247484)
• Results show Low frequency of AXIN2 mutations in patients with multiple polyposis. (PMID:16941501)
• The identification of a beta-catenin-T-cell factor-regulated Axin2-GSK3beta-Snail1 axis provides new mechanistic insights into cancer-associated epithelial-mesenchymal transition programmes. (PMID:17072303)
• AXIN1, AXIN2 and TCF7L2 may have roles in development of colorectal carcinomas [review] (PMID:17143297)
• Findings indicate that mutations of AXIN2 can lead to an oncogenic activation of the Wnt pathway in medulloblastomas. (PMID:17373666)
• Mutatated Axin2 can not form dimers, disturbs the degradation of beta-catenin, and leads to the nuclear accumulation of beta-catenin and activation of Wnt signaling pathway. (PMID:17927870)
• Mutations in AXIN1 and AXIN2 may contribute to gastric carcinogenesis. (PMID:18330950)
• a high level of p53 downregulates the beta-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer. (PMID:18372914)
• Germline AXIN2 mutation is associated with melanoma (PMID:18384130)
• Only borderline results for the association of AXIN2 and CDH1 with oral clefts with and without tooth agenesis. (PMID:18683894)
• Five snps in AXIN2 were associated with increased breast cancer risk. AXIN2 rs4791171 was significantly associated with risk in premenopausal women. (PMID:18708403)
• Frameshift mutations of Wnt pathway genes AXIN2 and TCF4 in gastric carcinomas with high microsatellite instability are reported. (PMID:18755497)
• Results support a role of AXIN2 in human tooth agenesis and for the first time suggests AXIN2 is involved in sporadic forms of common incisor agenesis. (PMID:18790474)
• The rs8081536 allelic variation in AXIN2 gene does not contribute to the susceptibility of HSCR in the patients. AXIN2 rs2240308 and rs9913621 allelic variation might be related to HSCR. (PMID:19065536)
• a gene that when mutated increases susceptibility to colon cancer also is associated with cleft lip and palate (PMID:19119171)
• Axin2 regulates chondrocyte maturation and axial skeletal development (PMID:19623616)
• AXIN2 has ben implicated int he mixed form of tooth agenesis. (PMID:19816326)
• The data indicate that conductin regulate centrosomal cohesion by altering the phosphorylation status of beta-catenin at the centrosomes. (PMID:20300119)
• the AXIN2 Intron2 rs35285779 single nucleotide polymorphism (SNP) is associated with development of prostate cancer as a protective SNP (PMID:21069480)
• Molecular analysis disclosed six distinct heterozygous AXIN2 variations in familial melanoma subjects. (PMID:21294210)
• axin associates with ubiquitin-specific protease 34 (USP34); results indicate USP34 controls the levels of axin and positively modulate Wnt signaling by acting downstream of beta-catenin stabilization through controlling the nuclear accumulation of axin (PMID:21383061)
• novel Axin 2 gene mutations may be a predisposing factor in ethnic Kashmiri population to colorectal cancer (PMID:21541676)
• a cohort of 93 Swedish probands with non-syndromic, isolated oligodontia, mutations were identified in the EDARADD), AXIN2, MSX1, and PAX9 genes (PMID:21626677)
• AXIN2, a Wnt target gene, showed increased expression in all serous ovarian cancer samples. (PMID:21666490)
• The results of this study indicated that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process. (PMID:21706018)
• The present study reports, for the first time, that AXIN2 genetic defects may be found in adrenocortical tumors. (PMID:21733995)
• RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins (PMID:21799911)
• CDC20-mediated degradation of conductin regulates Wnt/beta-catenin signalling for maximal activity during G1/S. (PMID:22322943)
• results continue to support a role for AXIN2 in the etiology of human clefting (PMID:22370446)
• Axin2 acts as a potent promoter of carcinoma behavior by up-regulating the activity of the transcriptional repressor, Snail1, inducing a functional epithelial-mesenchymal transition (EMT) program and driving metastatic activity (PMID:22745173)
• Borderline association with a decreased risk of cleft lip with or without cleft palate was observed for the AXIN2 rs3923087 variant. (PMID:22887353)
• tooth agenesis had increased risk of a family history of cancer. tooth agenesis was associated with positive self-reported family history of cancer and variants in AXIN2. (PMID:23169889)
• CDX2 activated APC and AXIN2 promoter activities via intestinal cell-specific enhancer elements; results suggest that a low CDX2 level has influence on the Wnt signaling in invasive colon cancer cells possibly promoting cellular migration (PMID:23393221)
• rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. (PMID:23516639)
• Axin2 regulates nuclear GSK-3 localization and Snail mediated E-cadherin promoter activity in colorectal cancer cells. (PMID:23624843)
• The generally increased expression of axin 2 in all tumor stages as compared to normal tissue suggests an initiating pathogenic function in the development of colorectal carcinoma. (PMID:23702820)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	axin2	ENSDARG00000100149
mus_musculus	Axin2	ENSMUSG00000000142
rattus_norvegicus	Axin2	ENSRNOG00000055010

Paralogs (23): RGS11 (ENSG00000076344), RGS1 (ENSG00000090104), RGS17 (ENSG00000091844), AXIN1 (ENSG00000103126), RGS9 (ENSG00000108370), RGS2 (ENSG00000116741), RGS4 (ENSG00000117152), RGSL1 (ENSG00000121446), RGS13 (ENSG00000127074), RGS22 (ENSG00000132554), RGS8 (ENSG00000135824), RGS3 (ENSG00000138835), RGS5 (ENSG00000143248), RGS16 (ENSG00000143333), RGS20 (ENSG00000147509), RGS10 (ENSG00000148908), RGS18 (ENSG00000150681), RGS12 (ENSG00000159788), RGS14 (ENSG00000169220), RGS19 (ENSG00000171700), RGS6 (ENSG00000182732), RGS7 (ENSG00000182901), RGS21 (ENSG00000253148)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1270862) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 43 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal neurocranium morphology	1
abnormal heart morphology	1
shortened head	1
abnormal cranium morphology	1
polydactyly	1
kinked tail	1
exencephaly	1
open neural tube	1
decreased body length	1
persistence of hyaloid vascular system	1
anophthalmia	1
microphthalmia	1
abnormal embryo development	1
abnormal embryo size	1
embryonic growth arrest	1
postnatal growth retardation	1
abnormal eye morphology	1
abnormal limb morphology	1
abnormal tail morphology	1
abnormal skeleton development	1
abnormal primitive streak morphology	1
curly tail	1
abnormal body wall morphology	1
premature intramembranous bone ossification	1
abnormal facial morphology	1

+18 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q0P5H5	95.3%	Diamond
Sus scrofa	Q3S853	95.3%	Diamond
Xenopus laevis	A1A643	91.5%	Diamond
Xenopus tropicalis	Q5M8L6	91.5%	Diamond
Gallus gallus	O42400	77.3%	Diamond
Drosophila melanogaster	P51140	49.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC02563	ncRNA	105827617
RGS9	protein-coding	8787
CEP112	protein-coding	201134
APOH	protein-coding	350

Protein

Protein identifiers

Axin-2 — Q9Y2T1 (reviewed: Q9Y2T1)

Alternative names: Axin-like protein, Axis inhibition protein 2, Conductin

All UniProt accessions (6): Q9Y2T1, A0A1B0GX50, E7ES00, F5GX43, J3QQJ3, J3QRK4

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitor of the Wnt signaling pathway. Down-regulates beta-catenin. Probably facilitate the phosphorylation of beta-catenin and APC by GSK3B.

Subunit / interactions. Interacts with glycogen synthase kinase-3 beta (GSK3B) and beta-catenin. The interaction between axin and beta-catenin occurs via the armadillo repeats contained in beta-catenin. Interacts with SMAD7 and RNF111. Interacts with ANKRD6. Interacts with SIAH1. Interacts with SIAH2.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in brain and lymphoblast.

Post-translational modifications. Probably phosphorylated by GSK3B and dephosphorylated by PP2A. ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination and subsequent activation of the Wnt signaling pathway. Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation and subsequent activation of the Wnt signaling pathway. Deubiquitinated by USP34, deubiquitinated downstream of beta-catenin stabilization step: deubiquitination is important Wnt signaling to positively regulate beta-catenin (CTNBB1)-mediated transcription.

Disease relevance. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The gene represented in this entry is involved in disease pathogenesis. Oligodontia-colorectal cancer syndrome (ODCRCS) [MIM:608615] Affected individuals manifest severe tooth agenesis and colorectal cancer or precancerous lesions of variable types. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The tankyrase-binding motif (also named TBD) is required for interaction with tankyrase TNKS and TNKS2.

RefSeq proteins (2): NP_001350742, NP_004646* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001158	DIX	Domain
IPR014936	Axin_b-cat-bd	Domain
IPR016137	RGS	Domain
IPR024066	RGS_subdom1/3	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR032101	Axin_TNKS-bd	Domain
IPR036305	RGS_sf	Homologous_superfamily
IPR038207	DIX_dom_sf	Homologous_superfamily
IPR043581	Axin-like	Family
IPR044926	RGS_subdomain_2	Homologous_superfamily

Pfam: PF00615, PF00778, PF08833, PF16646

UniProt features (22 total): region of interest 8, sequence conflict 5, compositionally biased region 4, domain 2, chain 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
8HEO	Crystal structure of SIAH1 SBD bound to Axin2 peptide	X-RAY DIFFRACTION	2.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2T1-F1	61.71	0.24

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Mutated cancer genes, Mutational cancer driver genes, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm; plasma membrane

Antibody reliability (HPA): IH approved · IF uncertain

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 13; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

13 pathways:

ID	Pathway	Evidence
R-HSA-4411364	Binding of TCF/LEF:CTNNB1 to target gene promoters	curated
R-HSA-9943962	CHD6, CHD7, CHD8, CHD9 subfamily	curated
R-HSA-4086398	Ca2+ pathway	curated
R-HSA-4641257	Degradation of AXIN	curated
R-HSA-201681	TCF dependent signaling in response to WNT	curated
R-HSA-5689880	Ub-specific processing proteases	curated
R-HSA-5688426	Deubiquitination	—
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-4641265	Repression of WNT target genes	electronic
R-HSA-162582	Signal Transduction	—
R-HSA-195721	Signaling by WNT	—

MSigDB gene sets: 459 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_AXIS_SPECIFICATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GCANCTGNY_MYOD_Q6

GO Biological Process (22): aortic valve morphogenesis (GO:0003180), mitral valve morphogenesis (GO:0003183), intracellular protein localization (GO:0008104), negative regulation of cell population proliferation (GO:0008285), dorsal/ventral axis specification (GO:0009950), positive regulation of epithelial to mesenchymal transition (GO:0010718), regulation of mismatch repair (GO:0032423), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), odontogenesis (GO:0042476), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), maintenance of DNA repeat elements (GO:0043570), positive regulation of fat cell differentiation (GO:0045600), mRNA stabilization (GO:0048255), cell development (GO:0048468), canonical Wnt signaling pathway (GO:0060070), regulation of centromeric sister chromatid cohesion (GO:0070602), cellular response to dexamethasone stimulus (GO:0071549), negative regulation of canonical Wnt signaling pathway (GO:0090090), regulation of extracellular matrix organization (GO:1903053), Wnt signaling pathway (GO:0016055), negative regulation of Wnt signaling pathway (GO:0030178), response to steroid hormone (GO:0048545)

GO Molecular Function (7): beta-catenin binding (GO:0008013), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), ubiquitin protein ligase binding (GO:0031625), molecular adaptor activity (GO:0060090), I-SMAD binding (GO:0070411), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), beta-catenin destruction complex (GO:0030877), protein-containing complex (GO:0032991)

Reactome top-level categories

10 top-level categories:

Category	Pathways
TCF dependent signaling in response to WNT	2
Signaling by WNT	1
Formation of the beta-catenin:TCF transactivating complex	1
Deubiquitination	1
CHD chromatin remodelers	1
Beta-catenin independent WNT signaling	1
Degradation of beta-catenin by the destruction complex	1
Signal Transduction	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

showing 60 of 62 GO namespaces:

Category	Terms
positive regulation of cell differentiation	2
protein binding	2
binding	2
cellular anatomical structure	2
aortic valve development	1
heart valve morphogenesis	1
mitral valve development	1
atrioventricular valve morphogenesis	1
macromolecule localization	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
axis specification	1
dorsal/ventral pattern formation	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of multicellular organismal process	1
regulation of DNA repair	1
mismatch repair	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
animal organ morphogenesis	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
DNA metabolic process	1
chromosome organization	1
fat cell differentiation	1
regulation of fat cell differentiation	1
regulation of mRNA stability	1
RNA stabilization	1
negative regulation of mRNA catabolic process	1
cell differentiation	1
anatomical structure development	1
cellular developmental process	1
Wnt signaling pathway	1
regulation of sister chromatid cohesion	1
centromeric sister chromatid cohesion	1
cellular response to glucocorticoid stimulus	1
response to dexamethasone	1
cellular response to ketone	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
extracellular matrix organization	1
regulation of cellular component organization	1
cell surface receptor signaling pathway	1
kinase binding	1
ubiquitin-like protein ligase binding	1
molecular_function	1
SMAD binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
membrane	1
cell periphery	1
intracellular protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 36 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
canonical Wnt signaling pathway	BP	mutant phenotype
intracellular protein localization	BP	direct assay
mRNA stabilization	BP	mutant phenotype
maintenance of DNA repeat elements	BP	mutant phenotype
negative regulation of canonical Wnt signaling pathway	BP	direct assay
odontogenesis	BP	mutant phenotype
positive regulation of epithelial to mesenchymal transition	BP	mutant phenotype
regulation of centromeric sister chromatid cohesion	BP	mutant phenotype
regulation of mismatch repair	BP	mutant phenotype
centrosome	CC	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
nucleus	CC	direct assay
enzyme binding	MF	physical interaction
ubiquitin protein ligase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,184 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AXIN2	CTNNB1	P35222	943
AXIN2	LEF1	Q9UJU2	874
AXIN2	WNT3A	P56704	862
AXIN2	DKK1	O94907	831
AXIN2	NKD1	Q969G9	827
AXIN2	CCND1	P24385	814
AXIN2	LRP6	O75581	814
AXIN2	GSK3B	P49841	807
AXIN2	MYC	P01106	795
AXIN2	DVL1	O14640	793
AXIN2	TCF7	P36402	787
AXIN2	LGR5	O75473	782
AXIN2	HNF4A	P41235	760
AXIN2	WNT5A	P41221	746
AXIN2	WNT4	P56705	743

IntAct

Human interaction partners of AXIN2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 66 partners by confidence:

Partner	Interaction type	MIscore	Records
GSK3B	physical association	0.820	2
GSK3A	association	0.660	2
PPP2CB	physical association	0.650	4
SMAD4	physical association	0.610	4
TGIF1	physical association	0.570	3
AMOT	physical association	0.560	3
AP1M1	physical association	0.560	3
BARD1	physical association	0.560	3
BTRC	physical association	0.560	3
BYSL	physical association	0.560	3
C2orf68	physical association	0.560	3
CAPN7	physical association	0.560	3
CCDC112	physical association	0.560	3
CHIC2	physical association	0.560	3
CTAG2	physical association	0.560	3
CWF19L2	physical association	0.560	3
ELOA	physical association	0.560	3
FAM161A	physical association	0.560	3
HOXB5	physical association	0.560	3
KIFC3	physical association	0.560	3
KRTAP10-10	physical association	0.560	3
KRTAP10-8	physical association	0.560	3
KRTAP4-5	physical association	0.560	3
KRTAP9-2	physical association	0.560	3
LNX1	physical association	0.560	3
MCRS1	physical association	0.560	3
PPP2R5A	physical association	0.560	3
PSMB2	physical association	0.560	3
SCNM1	physical association	0.560	3
STX11	physical association	0.560	3

BioGRID (127 interactions; top human partners by supporting records): GSK3B (Affinity Capture-MS; 11 records), GSK3A (Two-hybrid; 5 records), RNF146 (Affinity Capture-Western; 4 records), SIAH1 (Affinity Capture-Western; 4 records), ANKRD6 (Affinity Capture-Western; 3 records), BTRC (Two-hybrid; 2 records), CDC20 (Affinity Capture-Western; 2 records), CTNNB1 (Affinity Capture-MS; 2 records), HNRNPK (Affinity Capture-Western; 2 records), SMAD7 (Affinity Capture-Western; 2 records), AMBRA1 (Proximity Label-MS), AMOT (Two-hybrid), AP1M1 (Two-hybrid), APC (Affinity Capture-Western), APC2 (Two-hybrid)

SIGNOR signaling

15 signaling interactions:

A	Effect	B	Mechanism
AXIN2	down-regulates	CTNNB1
FHIT	“down-regulates quantity by repression”	AXIN2	“transcriptional regulation”
TNKS	“down-regulates quantity by destabilization”	AXIN2	ubiquitination
TNKS2	down-regulates	AXIN2	ubiquitination
XAV939	up-regulates	AXIN2
AXIN2	“up-regulates activity”	GSK3B/Axin/APC	binding
RNF146	“down-regulates quantity”	AXIN2	ubiquitination
RNF146	“down-regulates quantity by destabilization”	AXIN2	ubiquitination
TNKS2	“down-regulates quantity by destabilization”	AXIN2	ADP-ribosylation
TNKS	“down-regulates quantity by destabilization”	AXIN2	ADP-ribosylation
PLK1	“up-regulates activity”	AXIN2	phosphorylation
hsa-miR-582-3p	“down-regulates quantity by repression”	AXIN2	“post transcriptional regulation”
AXIN2	up-regulates	APC	binding
AXIN2	down-regulates	CTNNB1	binding
AXIN2	“up-regulates activity”	GSK3B	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Degradation of beta-catenin by the destruction complex	6	22.1×	3e-05
Deubiquitination	6	15.8×	1e-04
TCF dependent signaling in response to WNT	5	12.5×	2e-03
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	5	12.4×	2e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	10.3×	4e-03
EML4 and NUDC in mitotic spindle formation	5	9.9×	4e-03
Resolution of Sister Chromatid Cohesion	5	9.2×	5e-03
RHO GTPases Activate Formins	5	8.3×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	5	25.5×	5e-04
epidermal growth factor receptor signaling pathway	5	21.7×	8e-04
proteasome-mediated ubiquitin-dependent protein catabolic process	9	8.2×	5e-04
negative regulation of gene expression	6	7.3×	8e-03
positive regulation of gene expression	8	5.4×	6e-03

Disease & clinical

Genetic variants

Variant evidence for AXIN2: 4,361 ClinVar records (192 pathogenic / likely pathogenic); 2 PharmGKB clinical annotations; 7 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

4,361 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	161
Likely pathogenic	31
Uncertain significance	2326
Likely benign	812
Benign	107

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 192 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
545741	NM_004655.4(AXIN2):c.1994dup (p.Asn666fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
5881	NM_004655.4(AXIN2):c.1966C>T (p.Arg656Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
40260	NM_004655.4(AXIN2):c.1989G>A (p.Trp663Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
464561	NM_004655.4(AXIN2):c.1637del (p.Gly546fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
533194	NM_004655.4(AXIN2):c.1642G>T (p.Glu548Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
566626	NM_004655.4(AXIN2):c.1214_1215del (p.Glu405fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
599333	NM_004655.4(AXIN2):c.1460_1472dup (p.Pro494fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
664235	NM_004655.4(AXIN2):c.1912C>T (p.Gln638Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
936374	NM_004655.4(AXIN2):c.1249del (p.Ala417fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1415792	NM_004655.4(AXIN2):c.2023dup (p.Arg675fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1784003	NM_004655.4(AXIN2):c.1993_1994delinsT (p.Gly665fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
464585	NM_004655.4(AXIN2):c.194_195del (p.Pro65fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
533178	NM_004655.4(AXIN2):c.2309del (p.Phe770fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
577956	NM_004655.4(AXIN2):c.234G>A (p.Trp78Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
651751	NM_004655.4(AXIN2):c.730dup (p.Ser244fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2

Per-variant reference — Sugi Variant

Explore AXIN2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 1,003):

Position(s)	Effect	Δscore	Sites
17:65536318–65536319	donor_loss	1.0000	5
17:65537322–65537323	donor_loss	1.0000	4
17:65538201–65538202	donor_loss	1.0000	5
17:65538344–65538345	acceptor_loss	1.0000	6
17:65538353	acceptor_gain	1.0000
17:65549519	donor_loss	1.0000
17:65557804–65557805	donor_loss	1.0000	4
17:65530103–65530104	acceptor_loss	0.9900	3
17:65530104	acceptor_gain	0.9900
17:65533612	donor_gain	0.9900

AlphaMissense

1,431 missense substitutions predicted likely pathogenic (of 5,544 scored), across 348 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H442	8	0.995	0.999
F805	8	0.988	1.000
F110	8	0.987	0.999
F171	8	0.987	0.999
F791	8	0.983	1.000
F190	8	0.978	0.999
F95	8	0.973	0.999
D440	8	0.972	0.995
F117	8	0.971	1.000
F812	8	0.971	0.998
F112	8	0.957	0.997
F370	8	0.948	0.996
F818	8	0.938	0.997
F770	8	0.936	0.994
D109	8	0.930	0.983
D88	8	0.927	0.983
F17	8	0.888	0.985
H517	8	0.882	0.975
D310	8	0.881	0.967
D320	8	0.832	0.950

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Colon Adenocarcinoma, Rectum Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Rectum Adenocarcinoma (TCGA)	favorable	0.000189

Disease associations

OMIM: gene MIM:604025 | disease phenotypes: MIM:608615, MIM:114500, MIM:305100

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
oligodontia-cancer predisposition syndrome	Definitive	Autosomal dominant	4
craniosynostosis	Limited	Autosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
oligodontia-cancer predisposition syndrome	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (3 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

3 panels:

Panel	Rating
Ectodermal dysplasia	green
Inherited polyposis and early onset colorectal cancer - germline testing	amber
Rare syndromic craniosynostosis or isolated multisuture synostosis	amber

Mondo (7): AXIN2-related attenuated familial adenomatous polyposis (MONDO:0018426), oligodontia-cancer predisposition syndrome (MONDO:0012075), hereditary neoplastic syndrome (MONDO:0015356), colorectal cancer (MONDO:0005575), ectodermal dysplasia syndrome (MONDO:0019287), colon carcinoma (MONDO:0002032), craniosynostosis (MONDO:0015469)

Orphanet (5): AXIN2-related polyposis (Orphanet:401911), Oligodontia-cancer predisposition syndrome (Orphanet:300576), Inherited cancer-predisposing syndrome (Orphanet:140162), Ectodermal dysplasia syndrome (Orphanet:79373), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

22 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000677	Oligodontia
HP:0000968	Ectodermal dysplasia
HP:0001442	Typified by somatic mosaicism
HP:0002209	Sparse scalp hair
HP:0002215	Sparse axillary hair
HP:0002223	Absent eyebrow
HP:0002231	Sparse body hair
HP:0002891	Uterine leiomyosarcoma
HP:0003002	Breast carcinoma
HP:0003003	Colon cancer
HP:0005227	Adenomatous colonic polyposis
HP:0005584	Renal cell carcinoma
HP:0006716	Hereditary nonpolyposis colorectal carcinoma
HP:0006740	Transitional cell carcinoma of the bladder
HP:0006753	Neoplasm of the stomach
HP:0008070	Sparse hair
HP:0010764	Short eyelashes
HP:0033769	Fundic gland polyposis
HP:0100743	Neoplasm of the rectum
HP:0200063	Colorectal polyposis
HP:3000050	Abnormal odontoid tissue morphology

GWAS associations

7 associations:

Study	Trait	p-value
GCST006288_561	Heel bone mineral density	1e-14
GCST006979_693	Heel bone mineral density	3e-14
GCST008839_431	Height	1e-10
GCST006288_329	Heel bone mineral density	3e-9
GCST006988_99	Blond vs. brown/black hair color	1e-8
GCST010002_356	Refractive error	1e-8
GCST006288_278	Heel bone mineral density	2e-8

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0003924	hair color

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D004476	Ectodermal Dysplasia	C16.131.077.350; C16.131.831.350; C16.320.850.250; C17.800.804.350; C17.800.827.250
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C563898	Oligodontia-Colorectal Cancer Syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1255167 (SINGLE PROTEIN), CHEMBL3885520 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

2 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs11868547	Efficacy	3	Platinum compounds	Non-Small Cell Lung Carcinoma
rs4541111	Efficacy	3	Platinum compounds	Non-Small Cell Lung Carcinoma

PharmGKB variants

2 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4541111	AXIN2	3	3.00	1	Platinum compounds
rs11868547	AXIN2	3	3.00	1	Platinum compounds

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs11868547	Platinum compounds	Efficacy	Genotypes CC + CG is associated with increased overall survival when treated with Platinum compounds in people with Carcinoma, Non-Small-Cell Lung as compared to genotype GG.	PMID:24980784
rs4541111	Platinum compounds	Efficacy	Genotypes AA + AC is associated with increased overall survival when treated with Platinum compounds in people with Carcinoma, Non-Small-Cell Lung as compared to genotype CC.	PMID:24980784

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — β-catenin destruction complex proteins

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
CW85319	Binding	5.17	pKd

Binding affinities (BindingDB)

4 measured of 4 human assays (4 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-[4-(trifluoromethyl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol	EC50	371 nM
CHEMBL1867804	EC50	375 nM
CHEMBL1552719	EC50	566 nM
CHEMBL1898239	EC50	709 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.43	EC50	375	nM	CHEMBL1867804
6.43	EC50	371	nM	CHEMBL1086580
6.25	EC50	566	nM	CHEMBL1552719
6.15	EC50	709	nM	CHEMBL1898239

PubChem BioAssay actives

4 with measured affinity, of 23 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[4-(trifluoromethyl)phenyl]-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidin-4-one	656088: Stabilization of Axin2 in human SW480 cells after 24 hrs by sandwich ELISA	ec50	0.3710	uM
3-(3,4-dimethoxyphenyl)-5-[[4-(4-methoxyphenyl)-5-methyl-1,2,4-triazol-3-yl]sulfanylmethyl]-1,2,4-oxadiazole	656088: Stabilization of Axin2 in human SW480 cells after 24 hrs by sandwich ELISA	ec50	0.3750	uM
5-[[4-(4-methoxyphenyl)-5-pyridin-4-yl-1,2,4-triazol-3-yl]sulfanylmethyl]-3-(4-methylphenyl)-1,2,4-oxadiazole	656088: Stabilization of Axin2 in human SW480 cells after 24 hrs by sandwich ELISA	ec50	0.5660	uM
3-(4-methoxyphenyl)-5-[[4-(4-methoxyphenyl)-5-methyl-1,2,4-triazol-3-yl]sulfanylmethyl]-1,2,4-oxadiazole	656088: Stabilization of Axin2 in human SW480 cells after 24 hrs by sandwich ELISA	ec50	0.7090	uM

CTD chemical–gene interactions

60 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Niclosamide	decreases reaction, increases expression, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	3
Estradiol	decreases expression, decreases reaction, affects expression, affects cotreatment	3
Silicon Dioxide	increases expression, decreases expression, affects expression	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
bisphenol A	decreases expression, decreases methylation	2
Resveratrol	decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Quercetin	decreases expression	2
Lithium Chloride	increases expression, decreases reaction	2
p-carboxymethylphenyl 1,1-bis(3’-indolyl)-1-(p-carboxymethylphenyl)methane	affects binding, decreases reaction, increases reaction	1
multi-kinase inhibitor 108600	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
N,N-dimethylaniline	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
pyrvinium	decreases expression	1
cupric oxide	decreases expression	1
aeroplysinin I	decreases expression	1
casticin	increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression, decreases expression	1
CGP 52608	affects binding, increases reaction	1
broussochalcone A	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1267175	Binding	Induction of Axin2 accumulation in human DLD1 cells assessed as decrease in free beta-casein levels by Western blot analysis	Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. — *Nat Chem Biol*

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_7113	PR-Mel	Cancer cell line	Female
CVCL_D8HS	Ubigene HCT 116 AXIN2 KO	Cancer cell line	Male
CVCL_D8ZV	Ubigene HEK293 AXIN2 KO	Transformed cell line	Female
CVCL_D9YB	Ubigene HeLa AXIN2 KO	Cancer cell line	Female
CVCL_SE38	HAP1 AXIN2 (-) 1	Cancer cell line	Male
CVCL_XL84	HAP1 AXIN2 (-) 2	Cancer cell line	Male
CVCL_XL85	HAP1 AXIN2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 318 trials:

NCT	Phase	Status	Title
NCT00722436	Phase 4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	Phase 4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT00114829	Phase 4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	Phase 4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	Phase 4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	Phase 4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	Phase 4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	Phase 4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	Phase 4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	Phase 4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	Phase 4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	Phase 4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	Phase 4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	Phase 4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	Phase 4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	Phase 4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	Phase 4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	Phase 4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	Phase 4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	Phase 4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	Phase 4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	Phase 4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	Phase 4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	Phase 4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	Phase 4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	Phase 4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	Phase 4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	Phase 4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	Phase 4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	Phase 4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	Phase 4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	Phase 4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	Phase 4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	Phase 4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	Phase 4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	Phase 4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	Phase 4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	Phase 4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	Phase 4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	Phase 4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	Phase 4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	Phase 4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer
NCT02575378	Phase 4	UNKNOWN	Maintenance Treatment With Capecitabine Metronomic Chemotherapy and Chinese Traditional Medicine in Metastatic Colorectal Cancer
NCT02581423	Phase 4	COMPLETED	A Study of Capecitabine (Xeloda) in the Adjuvant Treatment of Participants With Resected Colon Cancer
NCT02582970	Phase 4	COMPLETED	A Study of Bevacizumab (Avastin) in Combination With Chemotherapy in Participants With Metastatic Cancer of the Colon or Rectum
NCT03084809	Phase 4	COMPLETED	Chemotherapy Combined With CIK Treating Colon Cancer
NCT03130634	Phase 4	COMPLETED	The Efficacy of Silymarin as Adjuvant Therapy on Colorectal Cancer Patients Undergoing FOLFIRI Treatment
NCT03298945	Phase 4	COMPLETED	Comparative Effectiveness of Split-Dose Colonoscopy Bowel Preparation Regimens
NCT03465202	Phase 4	UNKNOWN	Association of Capecitabine Pharmacokinetics and Toxicity With Aging
NCT03564938	Phase 4	COMPLETED	Regorafenib in Indian Patients With Metastatic Colorectal Cancer (mCRC).
NCT03700411	Phase 4	COMPLETED	Influence of Opioid Analgesia on Circulating Tumor Cells in Open Colorectal Cancer Surgery
NCT03700541	Phase 4	COMPLETED	Influence of Opioid Analgesia on Circulating Tumor Cells in Laparoscopic Colorectal Cancer Surgery
NCT03723447	Phase 4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT04074460	Phase 4	COMPLETED	Volatile Anaesthesia and Perioperative Outcomes Related to Cancer Feasibility Study
NCT04281667	Phase 4	ACTIVE_NOT_RECRUITING	Mechanical Bowel Preparation and Oral Antibiotics Versus Mechanical Bowel Preparation Only Prior Rectal Surgery
NCT04297423	Phase 4	COMPLETED	Two Low Volume Regimens for Colorectal Cancer Screening Colonoscopy
NCT04874207	Phase 4	COMPLETED	Evaluation of Treatment PERSOnalization Based on Its Therapeutic Monitoring in Patients With Metastatic Colorectal Cancer Treated With REgorafenib
NCT04874883	Phase 4	UNKNOWN	Effect of the Use of Symbiotics in Patients With Colon Cancer
NCT04973007	Phase 4	TERMINATED	Comparison of Contrast Agents in Liver Magnetic Resonance (MR) for the Detection of Hepatic Metastases
NCT05661357	Phase 4	UNKNOWN	Disitamab Vedotin Combined With Fruquintinib for mCRC With HER2 Expression

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for AXIN2 across ~30M SureChEMBL compounds — explore on Sugi Predict.