CDX2

Summary

CDX2 (caudal type homeobox 2, HGNC:1806) is a protein-coding gene on chromosome 13q12.2, encoding Homeobox protein CDX-2 (Q99626). Transcription factor which regulates the transcription of multiple genes expressed in the intestinal epithelium.

This gene is a member of the caudal-related homeobox transcription factor gene family. The encoded protein is a major regulator of intestine-specific genes involved in cell growth an differentiation. This protein also plays a role in early embryonic development of the intestinal tract. Aberrant expression of this gene is associated with intestinal inflammation and tumorigenesis.

Source: NCBI Gene 1045 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 56 total — 2 likely-pathogenic
• GTEx eGene: eQTL in 4 tissues, sQTL in 1 (q < 0.05)
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types (inferred from mutation patterns)
• Constraint (gnomAD): pLI 0.79 (intermediate), LOEUF 0.61 (unconstrained)
• Transcription factor: yes — 86 downstream targets (CollecTRI)
• MANE Select transcript: NM_001265
• Interaction hub: 1,966 STRING partners (top 8% of genes corpus-wide)
• Notable: 56 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1806
Approved symbol	CDX2
Name	caudal type homeobox 2
Location	13q12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000165556
Ensembl biotype	protein_coding
OMIM	600297
Entrez	1045

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000381020

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

ENST00000381020, ENST00000548877, ENST00000891171, ENST00000947371, ENST00001045881, ENST00001045882, ENST00001131598

RefSeq mRNA: 2 — MANE Select: NM_001265 NM_001265, NM_001354700

CCDS: CCDS9328

Canonical transcript exons

ENST00000381020 — 3 exons

Exon	Start	End
ENSE00001323854	27960918	27963369
ENSE00001487241	27968466	27969315
ENSE00003600647	27964870	27965015

Expression profiles

Bgee: expression breadth broad, 64 present calls, max score 98.57.

FANTOM5 (CAGE): breadth broad, TPM avg 3.9065 / max 3282.3832, expressed in 191 samples.

Highest expression (Bgee): mucosa of transverse colon, rectum, transverse colon, cervix squamous epithelium, small intestine Peyer’s patch.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CDX2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 4 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

5 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellar Hemisphere	eqtl	2.1e-13	+0.62	13:27990205:T:A
Prostate	eqtl	1.5e-09	-0.55	13:27966111:C:G
Brain Cerebellum	eqtl	9.3e-08	-0.52	13:27993035:A:C
Pancreas	eqtl	3.4e-04	+0.32	13:27940850:A:C
Colon Transverse	sqtl	5.5e-03	-0.40	13:27938582:G:A

FANTOM5 promoters

showing 10 of 12 alternative TSS:

Promoter ID	TPM avg	Samples expressed
136513	1.4403	129
136509	1.0684	142
136511	0.4097	88
136510	0.2743	77
136508	0.2403	72
136506	0.2049	6
136505	0.1085	3
136512	0.0961	39
136504	0.0252	3
136507	0.0171	4

Top tissues by expression

showing 100 of 262 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.57	gold quality
rectum	UBERON:0001052	96.28	gold quality
transverse colon	UBERON:0001157	87.82	gold quality
cervix squamous epithelium	UBERON:0006922	87.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.36	gold quality
duodenum	UBERON:0002114	85.46	gold quality
small intestine	UBERON:0002108	84.86	gold quality
colonic epithelium	UBERON:0000397	83.65	gold quality
colonic mucosa	UBERON:0000317	81.02	gold quality
ileal mucosa	UBERON:0000331	80.01	gold quality
cervix epithelium	UBERON:0004801	79.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	78.88	gold quality
heart right ventricle	UBERON:0002080	78.58	gold quality
vermiform appendix	UBERON:0001154	78.12	gold quality
jejunal mucosa	UBERON:0000399	77.51	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	76.90	gold quality
inferior olivary complex	UBERON:0002127	76.65	gold quality
intestine	UBERON:0000160	76.46	gold quality
caecum	UBERON:0001153	76.39	gold quality
parotid gland	UBERON:0001831	75.81	gold quality
frontal pole	UBERON:0002795	75.56	gold quality
paraflocculus	UBERON:0005351	75.07	gold quality
middle frontal gyrus	UBERON:0002702	74.40	gold quality
endometrium epithelium	UBERON:0004811	74.18	gold quality
large intestine	UBERON:0000059	73.70	gold quality
colon	UBERON:0001155	73.29	gold quality
body of pancreas	UBERON:0001150	71.59	gold quality
islet of Langerhans	UBERON:0000006	70.60	gold quality
pancreas	UBERON:0001264	70.01	gold quality
tongue squamous epithelium	UBERON:0006919	69.24	gold quality
gingival epithelium	UBERON:0001949	68.77	gold quality
middle temporal gyrus	UBERON:0002771	68.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	68.20	gold quality
Brodmann (1909) area 23	UBERON:0013554	67.98	gold quality
Brodmann (1909) area 46	UBERON:0006483	67.48	gold quality
squamous epithelium	UBERON:0006914	66.97	gold quality
orbitofrontal cortex	UBERON:0004167	66.26	gold quality
buccal mucosa cell	CL:0002336	66.17	gold quality
vastus lateralis	UBERON:0001379	65.84	gold quality
gingiva	UBERON:0001828	65.82	gold quality
cartilage tissue	UBERON:0002418	65.33	gold quality
oviduct epithelium	UBERON:0004804	65.31	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	64.95	gold quality
olfactory bulb	UBERON:0002264	64.56	gold quality
type B pancreatic cell	CL:0000169	64.39	gold quality
superficial temporal artery	UBERON:0001614	64.39	gold quality
choroid plexus epithelium	UBERON:0003911	64.26	gold quality
quadriceps femoris	UBERON:0001377	64.13	gold quality
jejunum	UBERON:0002115	63.83	gold quality
entorhinal cortex	UBERON:0002728	63.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	62.49	gold quality
nasal cavity epithelium	UBERON:0005384	62.30	gold quality
epithelium of esophagus	UBERON:0001976	62.20	gold quality
postcentral gyrus	UBERON:0002581	62.00	gold quality
decidua	UBERON:0002450	61.57	gold quality
tendon of biceps brachii	UBERON:0008188	61.18	gold quality
esophagus squamous epithelium	UBERON:0006920	59.87	gold quality
parietal pleura	UBERON:0002400	59.75	gold quality
visceral pleura	UBERON:0002401	59.56	gold quality
lateral nuclear group of thalamus	UBERON:0002736	59.28	gold quality
vena cava	UBERON:0004087	59.20	gold quality
pleura	UBERON:0000977	59.11	gold quality
biceps brachii	UBERON:0001507	58.85	gold quality
metanephric glomerulus	UBERON:0004736	58.83	gold quality
parietal lobe	UBERON:0001872	58.81	gold quality
renal glomerulus	UBERON:0000074	58.46	gold quality
mammalian vulva	UBERON:0000997	58.45	gold quality
myocardium	UBERON:0002349	57.79	gold quality
pancreatic ductal cell	CL:0002079	57.33	silver quality
nephron tubule	UBERON:0001231	56.98	gold quality
trabecular bone tissue	UBERON:0002483	56.47	gold quality
superior frontal gyrus	UBERON:0002661	56.29	gold quality
kidney epithelium	UBERON:0004819	56.12	gold quality
smooth muscle tissue	UBERON:0001135	55.69	gold quality
germinal epithelium of ovary	UBERON:0001304	55.42	gold quality
amniotic fluid	UBERON:0000173	55.25	gold quality
muscle tissue	UBERON:0002385	54.58	gold quality
sigmoid colon	UBERON:0001159	54.55	gold quality
skeletal muscle tissue	UBERON:0001134	54.43	gold quality
thymus	UBERON:0002370	54.01	gold quality
body of tongue	UBERON:0011876	53.88	gold quality
epithelial cell of pancreas	CL:0000083	53.49	gold quality
pigmented layer of retina	UBERON:0001782	53.36	gold quality
male germ cell	CL:0000015	52.95	gold quality
left ventricle myocardium	UBERON:0006566	52.69	gold quality
cerebellar vermis	UBERON:0004720	52.38	gold quality
metanephros	UBERON:0000081	52.34	gold quality
layer of synovial tissue	UBERON:0007616	52.19	gold quality
deltoid	UBERON:0001476	51.91	gold quality
corpus epididymis	UBERON:0004359	51.47	gold quality
sperm	CL:0000019	51.44	gold quality
epithelium of bronchus	UBERON:0002031	51.30	gold quality
oral cavity	UBERON:0000167	51.15	gold quality
fallopian tube	UBERON:0003889	51.12	gold quality
cardiac muscle of right atrium	UBERON:0003379	51.07	gold quality
tibia	UBERON:0000979	51.01	gold quality
caput epididymis	UBERON:0004358	50.97	gold quality
bronchus	UBERON:0002185	50.89	gold quality
bronchial epithelial cell	CL:0002328	50.63	gold quality
upper arm skin	UBERON:0004263	50.47	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	13.63
E-ANND-3	yes	8.24

HPA expression

RNA tissue specificity: Tissue enriched

11 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Colon	tissue	38.4	high
Small intestine	tissue	33.9	medium
Rectum	tissue	29.4	high
Duodenum	tissue	27.0	high
Appendix	tissue	4.7	high
Pancreas	tissue	1.4	not detected
Smooth muscle	tissue	1.0	not detected
Stomach 1	tissue	0.3	not detected
Seminal vesicle	tissue	0.1	not detected
Adipose tissue	tissue	0.1	not detected
Prostate	tissue	0.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 100; highest nTPM — Anterior thalamic nucleus, ventral (0.2), Area striata (white matter) (0.2), Nucleus rhomboideus (0.2), Anterior cingulate cortex, supragenual-ventral (0.1), Anterior cochlear nucleus, ventral (0.1).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 86 targets:

Target	Regulation
ABCB1	Unknown
ACAT2	Activation
ADAM2
ALPI	Repression
APC	Activation
ATOH1	Activation
ATRX
AXIN2	Activation
B3GALT5	Activation
BCL2	Activation
BMP4	Unknown
CA1	Unknown
CCL25	Activation
CCND1	Repression
CDH17	Activation
CDKN1A	Activation
CDKN2A
CDX1	Unknown
CDX2	Unknown
CDX4	Unknown
CEL
CFTR	Activation
CLDN1	Unknown
CLDN2	Activation
DPP4	Activation
DSC2	Unknown
ELMO3	Activation
FURIN	Unknown
FUT2	Activation
GCG	Unknown

JASPAR motifs

Motif	Name	Family
MA0465.1	CDX2	HOX
MA0465.2	CDX2	HOX
MA0465.3	CDX2	HOX

JASPAR matrix evidence (PMIDs): PMID:20696899

Upstream regulators (CollecTRI, top): AGR2, AHR, AP1, CDX1, CDX2, CTNNB1, FOS, FOXM1, GATA2, GATA3, GATA6, H19, HNF4A, JUN, KLF4, NANOG, NFKB1, NFKB, NR1H4, POU2F1, POU5F1, RELA, SMAD1, SMAD2, SMAD4, SOX2, SOX9, STAT3, TCF4, TCF7L2, TEAD4

miRNA regulators (miRDB)

Targeting CDX2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 86 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488

Functional genomics

gnomAD constraint: pLI 0.788, LOEUF 0.609, missense Z -0.0146 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000381020 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
13:27,963,118–27,963,264	58 / 59.4	0.98	no
13:27,963,265–27,968,500	64 / 124.6	0.51	no
13:27,968,501–27,969,006	253 / 247.5	1.02	no

Literature-anchored findings (GeneRIF, showing 40)

• Markedly reduced or absent CDX2 expression was noted by immunohistochemistry in 13 of 15 (87%) large cell minimally differentiated carcinomas (LCMDCs), whereas only 1 of the 25 (4%) differentiated adenocarcinomas (DACs)showed reduced CDX2 expression. (PMID:11733373)
• Increased CDX2 mRNA is associated with chronic atrophic gastritis (PMID:11846061)
• expression of CDX2 precedes expression of CDX1 during the progression of intestinal metaplasia;expression of CDX2 may trigger the initiation and development of intestinal metaplasia (PMID:11871772)
• The homeobox gene belongs to the p53-p21(WAF)-Bcl-2 network in intestinal epithelial cells (PMID:12270138)
• These results suggest that CDX2, but not CDX1, interacts with the MUC2 promoter and activates MUC2 transcription, and plays an important role in the differentiation of goblet cells. (PMID:12559945)
• findings suggest caudal type homeo box transcription factor 2(CDX2) inactivation in colon cancer results from defects in trans-acting pathways regulating CDX2 transcription, and CDX2 silencing contributes to altered phenotype of some colorectal cancers (PMID:12947088)
• A Cdx-2 binding site polymorphism (G to A) in the promoter region of the vitamin D receptor gene was reported. investigated the relationship between the VDR Cdx-2 genotype and risk of fracture (PMID:12968672)
• p21 is a transcriptional target of CDX2. Our results may thus provide a new mechanism underlying the functions of CDX2. (PMID:12970742)
• Cdx-2 activates the expression of MUC2 mucin gene in gastric cells, inducing an intestinal transdifferentiation phenotype that parallels what is observed both in intestinal metaplasia and some gastric carcinomas (PMID:14525978)
• results suggest that Cdx2 is a useful prognostic marker for gastric cancer; advanced gastric cancers with both intestinal and gastric phenotypic expression have a relatively good prognosis (PMID:14557879)
• Cdx2 protein is a sensitive marker of intestinal metaplasia in the upper gastrointestinal tract and may be useful in detecting histologically equivocal cases of Barrett’s esophagus. (PMID:14576477)
• These results show that Cdx1 and Cdx2 might be indispensable for intestinal phenotypic expression even in gastric cancer cells (PMID:14615935)
• Aberrant expression of CDX2 is closely related to the overexpression of MUC2 in mucinous intrahepatic cholangiocarcinoma and intraductal papillary neoplasia of the liver associated with hepatolithiasis. (PMID:15048136)
• Cdx2 is a highly sensitive marker for Barrett’s esophagus. (PMID:15167938)
• APC and CDX2 have roles in controlling retinoic acid biosynthesis and in promoting a retinoid-induced program of colonocyte differentiation (PMID:15190067)
• CDX2 is a sensitive and specific marker for colorectal adenocarcinoma. (PMID:15205684)
• Cdx1 and Cdx2 inhibit colon cancer cell proliferation by blocking beta-catenin/TCF transcriptional activity (PMID:15215241)
• Cdx-2 is a permissive factor that influences basal CaBP expression in enterocytes and that HNF-1alpha modulates CaBP gene expression during cellular differentiation. (PMID:15217781)
• CDX2 and MUC2 genes are repressed by SOX9 in intestinal epithelium (PMID:15240568)
• identification of MOK, a member of the mitogen-activated protein kinase superfamily, as one of the genes induced by a caudal-related homeobox transcription factor, Cdx2 (PMID:15327990)
• a sensitive and specific marker for differentiating metastatic colorectal adenocarcinoma from mucinous bronchioloalveolar adenocarcinoma. (PMID:15362373)
• There is a transient loss of Cdx2 in budding tumor cells at the tumor host interface in colorectal cancer, and reexpression of Cdx2 in metastases. (PMID:15466189)
• CDX2 may be considered a sensitive and specific marker of midgut serotonin-producing /EC/-cells and EC-cell tumors, and its expression may be useful in the diagnosis of metastases from occult ETs (PMID:15517368)
• Cdx2 expression in invasive ductal carcinomas may be a novel prognostic marker for patient survival. (PMID:15547744)
• the major factors determining the presence of CDX-2 in colorectal carcinomas at the protein product level may include cancer location and the solid phenotype of the tumor. (PMID:15619975)
• CDX2 plays an important role in gallbladder carcinogenesis with intestinal differentiation. (PMID:15645288)
• Study suggests that CDX2 is a relatively specific marker for tumors with intestinal differentiation; it can be seen in large cell and adenocarcinomas of the lung. (PMID:15722794)
• Cdx1 activates the IAP gene via a novel cis element, whereas Cdx2 inhibits the Cdx1 effects (PMID:15774940)
• Aberrant expression of cdx2 homeobox gene was detected in pancreatic intraductal papillary mucinous neoplasm but not in ductal adenocarcinoma (PMID:15782100)
• marker for cellular phenotype in sinonasal intestinal-type adenocarcinoma (PMID:15894926)
• CDX2 expression levels were strongly associated with microsatellite instability and tumor location in the gastrointestinal tract, consistent with a possible role in the specification of gastrointestinal epithelial cell fate in humans. (PMID:15994917)
• Phosphorylation of CDX2 mediates its ubiquitin-dependent proteasome degradation. (PMID:16027724)
• Higher expression of Cdx2 is associated with intestinal-type carcinomas (PMID:16144916)
• CDX2 mRNA and CDX2 protein expression are upregulated in Barrett’s IM tissues, compared with normal squamous esophagus, and remain elevated in dysplasia and adenocarcinoma tissues (PMID:16291394)
• disruption of CDX2 in MKN45 cells does not significantly affect their tumorigenic potential (PMID:16331267)
• The loss of Cdx2 expression or transcriptional activity is an infrequent event during tumorigenesis, which does not contribute to molecular mechanisms underlying initiation and progression of most colorectal tumors. (PMID:16361536)
• Cdx2 requires additional factors to activate the enterocyte differentiation program in normal undifferentiated cells (PMID:16480684)
• CDX-2 expression in stomach cancer may be a marker of the progression of gastric carcinogenesis, and that its activation may represent an early event. (PMID:16509871)
• Transformation associated with reflux at the gastroesophageal junction reflects activation by bile acid and acid of a transcriptional program involving NF-kappaB and Cdx2, which mediate intestinal metaplasia and ectopic expression of GC-C. (PMID:16618413)
• Cdx2 was shown to cooperatively activate the UGT2B7 promoter in conjunction with hepatocyte nuclear factor 1alpha (HNF1alpha), a mechanism previously observed to regulate other intestine-specific genes. (PMID:16788384)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cdx2	ENSMUSG00000029646
rattus_norvegicus	Cdx2	ENSRNOG00000032759

Paralogs (2): CDX1 (ENSG00000113722), CDX4 (ENSG00000131264)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88361) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 67 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal rib morphology	2
abnormal cecum morphology	2
abnormal colon morphology	2
short tail	2
vertebral transformation	2
embryonic lethality before implantation, complete penetrance	2
abnormal intestine morphology	1
absent enterocytes	1
abnormal intestinal epithelium morphology	1
abnormal crypts of Lieberkuhn morphology	1
abnormal small intestine morphology	1
abnormal intestinal mucosa morphology	1
kinked tail	1
decreased body weight	1
decreased body size	1
abnormal mesoderm development	1
absent trophoblast giant cells	1
abnormal placenta labyrinth morphology	1
failure of embryo implantation	1
embryonic growth arrest	1
increased colon hamartoma incidence	1
increased colon adenoma incidence	1
increased intestinal adenoma incidence	1
abnormal ileum morphology	1
abnormal cell migration	1

+42 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
Gallus gallus	P46692	99.6%	Diamond
Mesocricetus auratus	Q04649	96.0%	Diamond
Pongo pygmaeus	A2T7H5	95.1%	Diamond
Xenopus tropicalis	Q90X89	94.7%	Diamond
Xenopus laevis	Q91622	94.7%	Diamond
Lineus sanguineus	P81193	88.3%	Diamond
Drosophila melanogaster	P09085	86.4%	Diamond
Caenorhabditis briggsae	A8XSQ8	80.7%	Diamond
Caenorhabditis elegans	P34766	80.4%	Diamond
Nakaseomyces glabratus CBS 138	Q708A7	48.9%	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
PDX1	protein-coding	3651
URAD	protein-coding	646625
LINC00543	ncRNA	100132234
FLT3	protein-coding	2322
PLUT	ncRNA	100861550

Protein

Protein identifiers

Homeobox protein CDX-2 — Q99626 (reviewed: Q99626)

Alternative names: CDX-3, Caudal-type homeobox protein 2

All UniProt accessions (1): Q99626

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor which regulates the transcription of multiple genes expressed in the intestinal epithelium. Binds to the promoter of the intestinal sucrase-isomaltase SI and activates SI transcription. Binds to the DNA sequence 5’-ATAAAAACTTAT-3’ in the promoter region of VDR and activates VDR transcription. Binds to and activates transcription of LPH. Activates transcription of CLDN2 and intestinal mucin MUC2. Binds to the 5’-AATTTTTTACAACACCT-3’ DNA sequence in the promoter region of CA1 and activates CA1 transcription. Important in broad range of functions from early differentiation to maintenance of the intestinal epithelial lining of both the small and large intestine. Binds preferentially to methylated DNA.

Subunit / interactions. Can bind DNA as a monomer or homodimer.

Subcellular location. Nucleus.

Tissue specificity. Detected in small intestine, colon and pancreas.

Post-translational modifications. Ubiquitinated, leading to its degradation by the proteasome. Phosphorylation at Ser-60 reduces transactivation capacity. Phosphorylation at Ser-283 reduces transactivation capacity and also increases ubiquitin-dependent proteasome degradation.

Similarity. Belongs to the Caudal homeobox family.

RefSeq proteins (2): NP_001256, NP_001341629 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR006820	Caudal_activation_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR047152	Caudal_homeobox	Family

Pfam: PF00046, PF04731

UniProt features (19 total): helix 4, sequence conflict 3, region of interest 3, compositionally biased region 2, modified residue 2, chain 1, DNA-binding region 1, sequence variant 1, strand 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
6ES3	Structure of CDX2-DNA(TCG)	X-RAY DIFFRACTION	2.57
5LTY	Homeobox transcription factor CDX2 bound to methylated DNA	X-RAY DIFFRACTION	2.66
6ES2	Structure of CDX2-DNA(CAA)	X-RAY DIFFRACTION	2.95
7Q4N	transcription factor CDX2 bound to hydroxymethylated DNA	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99626-F1	63.77	0.22

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Helix-turn-helix domains, Cancer-related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol; vesicles

Antibody reliability (HPA): IH enhanced · IF approved

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)

Type	Positions
Phosphoserine	60, 283

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-2892245	POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	curated
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	curated
R-HSA-400508	Incretin synthesis, secretion, and inactivation	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-2980736	Peptide hormone metabolism	—

MSigDB gene sets: 175 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_VACUOLAR_TRANSPORT, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (15): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of cell population proliferation (GO:0008284), embryonic pattern specification (GO:0009880), animal organ morphogenesis (GO:0009887), anterior/posterior axis specification (GO:0009948), regulation of somitogenesis (GO:0014807), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), digestive tract development (GO:0048565), intestinal epithelial cell differentiation (GO:0060575), regulation of DNA-templated transcription (GO:0006355), multicellular organism development (GO:0007275), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (11): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), methyl-CpG binding (GO:0008327), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (5): chromatin (GO:0000785), condensed nuclear chromosome (GO:0000794), nucleus (GO:0005634), transcription repressor complex (GO:0017053), protein-containing complex (GO:0032991)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Incretin synthesis, secretion, and inactivation	1
Metabolism of proteins	1
Peptide hormone metabolism	1
Transcriptional regulation of pluripotent stem cells	1

GO top-level categories

54 GO namespaces:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
DNA-templated transcription	2
transcription cis-regulatory region binding	2
sequence-specific DNA binding	2
DNA binding	2
negative regulation of DNA-templated transcription	1
gene expression	1
RNA biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
pattern specification process	1
embryo development	1
anatomical structure morphogenesis	1
animal organ development	1
axis specification	1
anterior/posterior pattern specification	1
somitogenesis	1
regulation of anatomical structure morphogenesis	1
regulation of multicellular organismal process	1
cellular developmental process	1
positive regulation of DNA-templated transcription	1
tube development	1
digestive system development	1
animal gross anatomical part developmental process	1
columnar/cuboidal epithelial cell differentiation	1
digestive tract development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
multicellular organismal process	1
anatomical structure development	1
positive regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription regulator activity	1
nucleotide binding	1
double-stranded DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
nuclear chromosome	1
condensed chromosome	1
nucleus	1
intracellular membrane-bounded organelle	1
transcription regulator complex	1
cellular_component	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 31 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of transcription by RNA polymerase II	BP	direct assay
DNA-binding transcription repressor activity, RNA polymerase II-specific	MF	direct assay
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay
methyl-CpG binding	MF	direct assay
sequence-specific double-stranded DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,966 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDX2	KRT20	P35900	911
CDX2	LIAT1	Q6ZQX7	885
CDX2	KRT7	P08729	883
CDX2	MUC2	Q02817	840
CDX2	GATA6	P78327	834
CDX2	SOX17	Q9H6I2	803
CDX2	POU5F1	P31359	778
CDX2	ESRRB	O95718	769
CDX2	PAX8	Q06710	755
CDX2	HNF1A	P20823	751
CDX2	MUC6	Q6W4X9	751
CDX2	FOXA2	Q9Y261	746
CDX2	GATA3	P23771	736
CDX2	NAPSA	O96009	733
CDX2	SOX2	P48431	719

IntAct

Human interaction partners of CDX2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
CFAP206	physical association	0.560	3
KRTAP4-12	physical association	0.560	3
H1-5	physical association	0.400	1
IPO8	association	0.350	1
MEP1A	association	0.350	1

BioGRID (44 interactions; top human partners by supporting records): PAX6 (Reconstituted Complex; 4 records), EP300 (Reconstituted Complex; 3 records), RELA (Affinity Capture-Western; 3 records), ATM (Reconstituted Complex; 2 records), KDM5B (Affinity Capture-Western; 2 records), SMARCA2 (Reconstituted Complex; 2 records), BTF3 (Affinity Capture-MS), C6orf165 (Two-hybrid), CDK2 (Biochemical Activity), DNMT3L (Reconstituted Complex), EGLN3 (Affinity Capture-MS), FBXW7 (Affinity Capture-Western), FOXE1 (Affinity Capture-MS), GSK3B (Affinity Capture-Western), HIST1H1B (Cross-Linking-MS (XL-MS))

SIGNOR signaling

showing 19 of 28 signaling interactions:

A	Effect	B	Mechanism
CDK2	“down-regulates quantity by destabilization”	CDX2	phosphorylation
CDX2	“up-regulates quantity by expression”	VIL1	“transcriptional regulation”
MAPK14	“down-regulates quantity by destabilization”	CDX2	phosphorylation
GATA6	“up-regulates quantity by expression”	CDX2
SOX9	“down-regulates quantity by repression”	CDX2	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	CDH17	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	MEP1A	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	UGT1A10	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	UGT1A8	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	FUT2	“transcriptional regulation”
NANOG	“down-regulates quantity by repression”	CDX2	“transcriptional regulation”
PDHX	“down-regulates activity”	CDX2	binding
CDX2	“up-regulates quantity by expression”	INS	“transcriptional regulation”
POU5F1	“down-regulates quantity by repression”	CDX2	“transcriptional regulation”
CDX2	“form complex”	CDX2/PAX6/P300	binding
GSK3B	unknown	CDX2	phosphorylation
CDX2	“up-regulates quantity by expression”	LCT	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	MUC2	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	TFF3	“transcriptional regulation”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ CDX2-FBXW7-GSK3B complex	3	CDX2, FBXW7, GSK3B

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — ESCA.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for CDX2: 56 ClinVar records (2 pathogenic / likely pathogenic); 1 CIViC cancer variant; 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	51
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (2)

Showing all 2 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
812557	NM_001265.6(CDX2):c.940T>C (p.Ter314Arg)	Likely pathogenic	criteria provided, single submitter	1
145957	GRCh38/hg38 13q12.13-12.3(chr13:26965244-30097858)x3	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore CDX2’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; 25 predictions of 293):

Position(s)	Effect	Δscore	Sites
13:27963370–27963371	acceptor_loss	1.0000	4
13:27963376	acceptor_gain	1.0000
13:27964911	donor_gain	1.0000
13:27965016–27965017	acceptor_loss	1.0000	6
13:27965018	acceptor_gain	1.0000
13:27963371	acceptor_loss	0.9900
13:27964902	donor_gain	0.9900
13:27968464–27968465	donor_loss	0.9900	4
13:27963370	acceptor_loss	0.9800
13:27964868–27964869	donor_loss	0.9800	5

AlphaMissense

766 missense substitutions predicted likely pathogenic (of 2,012 scored), across 184 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
N236	8	1.000	1.000
F234	8	0.999	1.000
F205	8	0.992	1.000
D195	8	0.991	0.999
D187	8	0.983	0.999
H206	8	0.963	0.999
S208	8	0.914	1.000
E202	7	1.000	1.000
I232	7	1.000	1.000
W233	7	1.000	1.000
E204	7	0.999	1.000
Q235	7	0.999	1.000
R184	7	0.998	1.000
R215	7	0.998	1.000
R228	7	0.998	1.000
K231	7	0.998	1.000
E200	7	0.997	1.000
R242	7	0.997	1.000
K216	7	0.995	1.000
E227	7	0.995	1.000

HPA cancer prognostics

RNA cancer specificity: Group enriched (Colon Adenocarcinoma, Rectum Adenocarcinoma)

Disease associations

OMIM: gene MIM:600297 | disease phenotypes:

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
Fetal anomalies	green
Limb disorders	green
Paediatric disorders	green
VACTERL-like phenotypes	green
Non-syndromic familial congenital anorectal malformations	amber

Mondo (1): sirenomelia (MONDO:0017850)

Orphanet (1): Sirenomelia (Orphanet:3169)

GWAS associations

3 associations:

Study	Trait	p-value
GCST004625_29	Monocyte count	1e-27
GCST002553_1	Pancreatic cancer	2e-9
GCST005951_14	Body mass index	2e-8

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

CIViC curated variants (1)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

EXPRESSION.

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases reaction, increases expression, affects cotreatment, increases reaction, affects reaction	3
6-formylindolo(3,2-b)carbazole	increases expression, increases reaction, affects cotreatment, decreases reaction	2
Decitabine	increases expression, decreases methylation, decreases reaction, increases reaction, affects cotreatment	2
3,19-(2-bromobenzylidene)andrographolide	decreases response to substance, increases expression	1
trichostatin A	increases expression, increases reaction	1
indole-3-carbinol	increases expression, increases reaction	1
2-ethylhexyldiphenylphosphate	decreases expression	1
benzo(e)pyrene	decreases methylation	1
puag-haad	decreases reaction, increases expression	1
nitazoxanide	increases expression	1
santicizer 148	decreases expression	1
bisindolylmaleimide I	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
tizoxanide	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects expression	1
bisphenol S	decreases methylation	1
CL 075	increases expression, increases reaction	1
(+)-JQ1 compound	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	decreases expression	1
Acids	decreases methylation, increases expression	1
Benzo(a)pyrene	increases methylation	1
Bile Acids and Salts	increases expression	1
Chenodeoxycholic Acid	increases expression	1
Cholic Acids	decreases methylation, increases expression	1
Fluorouracil	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	decreases reaction, increases expression, affects cotreatment, affects reaction	1
Methapyrilene	decreases methylation	1

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0N1	SEES3-1V human CDX2, clone1	Embryonic stem cell	Male
CVCL_A0N2	SEES3-1V human CDX2, clone2	Embryonic stem cell	Male
CVCL_A0N3	SEES3-1V human CDX2, clone3	Embryonic stem cell	Male
CVCL_B8DJ	Abcam HCT 116 CDX2 KO	Cancer cell line	Male
CVCL_B8U1	Abcam MCF-7 CDX2 KO	Cancer cell line	Female
CVCL_B9FS	Abcam A-549 CDX2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

9 trials:

NCT	Phase	Status	Title
NCT03746834	Phase 4	COMPLETED	NASHA/Dx as a Perianal Implant for the Treatment of Persistent Fecal Incontience After Anorectal Malformation
NCT07392203	Early Phase 1	NOT_YET_RECRUITING	Role of (Saline- Glycerin) Rectal Enema in Treatment of Fecal Incontinence in Children
NCT00909415	Not specified	COMPLETED	Urodynamic Evaluation in Patients With Anorectal Malformation According to Spinal Cord Abnormalities
NCT02029248	Not specified	COMPLETED	National Study on the Quality of Life of Patients With Anorectal Malformation
NCT02624232	Not specified	UNKNOWN	Long-term Outcome in Patients With Anorectal Malformations
NCT03174028	Not specified	UNKNOWN	Laparoscopically Assisted Anorectal Pull-through Versus Posterior Sagittal Anorectoplasty
NCT03185637	Not specified	COMPLETED	Children’s Surgery in Sub-Saharan Africa
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT07603232	Not specified	ENROLLING_BY_INVITATION	Long-Term Health Outcomes in Children Born With Hirschsprung’s Disease and Anorectal Malformations at the Colorectal Centre of Excellence in Quebec