CRIPTO3

Summary

CRIPTO3 (cripto, EGF-CFC family member 3, HGNC:11703) is a protein-coding gene on chromosome Xq23, encoding Protein CRIPTO3 (P51864). Could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm.

The TDGF3 locus has characteristics of a retrotransposon, including lack of introns and a poly(A) sequence.

Source: NCBI Gene 6998 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 1 total
• GTEx eGene: eQTL in 1 tissue, sQTL in 0 (q < 0.05)
• MANE Select transcript: NM_001397362

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11703
Approved symbol	CRIPTO3
Name	cripto, EGF-CFC family member 3
Location	Xq23
Locus type	gene with protein product
Status	Approved
Aliases	TDGF2, CR-3, CRIPTO-3
Ensembl gene	ENSG00000225366
Ensembl biotype	protein_coding
Entrez	6998

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

MANE Select: ENST00000602699

ENST00000602699, ENST00000851044

RefSeq mRNA: 1 — MANE Select: NM_001397362 NM_001397362

CCDS: CCDS94651

Canonical transcript exons

ENST00000602699 — 1 exons

Exon	Start	End
ENSE00004283548	110520896	110523021

Expression profiles

Bgee: expression breadth broad, 23 present calls, max score 72.83.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, vastus lateralis, primordial germ cell in gonad, adrenal tissue, colonic epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CRIPTO3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 1 tissue and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

1 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adrenal Gland	eqtl	2.9e-03	+0.85	X:110916548:C:A

Top tissues by expression

showing 100 of 114 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.83	gold quality
vastus lateralis	UBERON:0001379	64.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	50.25	silver quality
adrenal tissue	UBERON:0018303	45.32	gold quality
colonic epithelium	UBERON:0000397	41.19	gold quality
adult mammalian kidney	UBERON:0000082	40.18	gold quality
kidney	UBERON:0002113	38.78	gold quality
skeletal muscle tissue	UBERON:0001134	38.73	gold quality
hindlimb stylopod muscle	UBERON:0004252	37.43	silver quality
left ovary	UBERON:0002119	37.30	silver quality
ovary	UBERON:0000992	37.07	silver quality
right lobe of liver	UBERON:0001114	36.57	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
sural nerve	UBERON:0015488	36.24	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
endometrium	UBERON:0001295	35.48	gold quality
muscle tissue	UBERON:0002385	34.99	gold quality
apex of heart	UBERON:0002098	34.88	gold quality
prefrontal cortex	UBERON:0000451	34.26	gold quality
spleen	UBERON:0002106	33.90	gold quality
right coronary artery	UBERON:0001625	33.64	gold quality
monocyte	CL:0000576	33.27	gold quality
mucosa of stomach	UBERON:0001199	33.18	gold quality
adrenal gland	UBERON:0002369	33.06	gold quality
bone marrow	UBERON:0002371	32.91	gold quality
leukocyte	CL:0000738	32.76	gold quality
left adrenal gland cortex	UBERON:0035825	32.67	gold quality
blood	UBERON:0000178	32.65	gold quality
superior frontal gyrus	UBERON:0002661	32.61	gold quality
gall bladder	UBERON:0002110	32.44	gold quality
metanephros cortex	UBERON:0010533	32.30	silver quality
right lung	UBERON:0002167	31.70	gold quality
left adrenal gland	UBERON:0001234	31.28	silver quality
corpus callosum	UBERON:0002336	31.20	gold quality
calcaneal tendon	UBERON:0003701	30.54	gold quality
tonsil	UBERON:0002372	30.52	gold quality
frontal cortex	UBERON:0001870	30.48	gold quality
primary visual cortex	UBERON:0002436	30.33	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
right adrenal gland cortex	UBERON:0035827	29.55	gold quality
thyroid gland	UBERON:0002046	29.41	gold quality
cerebellum	UBERON:0002037	29.35	gold quality
placenta	UBERON:0001987	29.31	gold quality
cerebellar cortex	UBERON:0002129	29.20	gold quality
lymph node	UBERON:0000029	28.94	gold quality
right uterine tube	UBERON:0001302	28.88	gold quality
cerebellar hemisphere	UBERON:0002245	28.83	gold quality
islet of Langerhans	UBERON:0000006	28.75	silver quality
right lobe of thyroid gland	UBERON:0001119	28.66	gold quality
thoracic mammary gland	UBERON:0005200	28.44	gold quality
fundus of stomach	UBERON:0001160	28.40	gold quality
left lobe of thyroid gland	UBERON:0001120	28.35	gold quality
heart left ventricle	UBERON:0002084	28.35	silver quality
cerebral cortex	UBERON:0000956	28.25	gold quality
duodenum	UBERON:0002114	28.14	gold quality
right hemisphere of cerebellum	UBERON:0014890	28.03	gold quality
nucleus accumbens	UBERON:0001882	27.84	gold quality
lower esophagus muscularis layer	UBERON:0035833	27.56	gold quality
brain	UBERON:0000955	27.45	silver quality
lower esophagus	UBERON:0013473	27.45	gold quality
multicellular organism	UBERON:0000468	27.28	silver quality
stomach	UBERON:0000945	27.24	gold quality
body of pancreas	UBERON:0001150	26.93	gold quality
uterine cervix	UBERON:0000002	26.91	gold quality
lung	UBERON:0002048	26.60	gold quality
vermiform appendix	UBERON:0001154	26.42	gold quality
esophagus	UBERON:0001043	26.22	gold quality
putamen	UBERON:0001874	26.13	gold quality
small intestine	UBERON:0002108	26.11	gold quality
temporal lobe	UBERON:0001871	26.04	gold quality
amygdala	UBERON:0001876	25.94	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	25.89	gold quality
hypothalamus	UBERON:0001898	25.86	gold quality
muscle layer of sigmoid colon	UBERON:0035805	25.82	gold quality
intestine	UBERON:0000160	25.72	gold quality
Brodmann (1909) area 9	UBERON:0013540	25.54	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	25.45	gold quality
colon	UBERON:0001155	25.33	gold quality
endocervix	UBERON:0000458	25.23	gold quality
right frontal lobe	UBERON:0002810	24.95	gold quality
popliteal artery	UBERON:0002250	24.93	gold quality
tibial artery	UBERON:0007610	24.90	gold quality
skin of abdomen	UBERON:0001416	24.65	gold quality
adipose tissue	UBERON:0001013	24.55	gold quality
body of stomach	UBERON:0001161	24.51	gold quality
small intestine Peyer’s patch	UBERON:0003454	24.49	gold quality
esophagus mucosa	UBERON:0002469	24.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	24.41	gold quality
omental fat pad	UBERON:0010414	24.25	gold quality
substantia nigra	UBERON:0002038	24.11	gold quality
zone of skin	UBERON:0000014	24.06	gold quality
upper lobe of left lung	UBERON:0008952	24.03	gold quality
skin of leg	UBERON:0001511	23.28	gold quality
vagina	UBERON:0000996	23.13	gold quality
pituitary gland	UBERON:0000007	23.04	gold quality
saliva-secreting gland	UBERON:0001044	23.02	gold quality
transverse colon	UBERON:0001157	22.99	gold quality
fallopian tube	UBERON:0003889	22.75	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	69.38
E-MTAB-9388	yes	11.65
E-ANND-3	yes	3.76

HPA expression

RNA tissue specificity: Not detected

21 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebellum	tissue	1.2
Cerebral cortex	tissue	0.9
Pons	tissue	0.8
Amygdala	tissue	0.8
Choroid plexus	tissue	0.8
Midbrain	tissue	0.8
Thalamus	tissue	0.8
Hypothalamus	tissue	0.8
Hippocampal formation	tissue	0.8
Postcentral gyrus	tissue	0.8
Basal ganglia	tissue	0.7
Putamen	tissue	0.7
Nucleus accumbens	tissue	0.7
Medulla oblongata	tissue	0.7
Occipital cortex	tissue	0.7
Locus coeruleus	tissue	0.6
Spinal cord	tissue	0.6
Retrosplenial cortex	tissue	0.6
Substantia nigra	tissue	0.5
Hippocampus	tissue	0.5
Spleen	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Flocculonodular lobe (1.2), Vermis (1.1), Anterior cingulate cortex, supragenual-ventral (0.9), Cerebellar cortex (0.9), Area striata (0.8).

Regulation

Is transcription factor: no

Functional genomics

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000602699 — one region, missense o/e 0.79.

Literature-anchored findings (GeneRIF, showing 3)

• CRIPTO-3, a processed pseudogene of CRIPTO-1 on the X chromosome, is expressed in undifferentiated NT2 cells and is regulated by germ cell nuclear factor in parallel to CRIPTO-1 (PMID:16954206)
• These data indicate that CRIPTO3 is an expressed gene, particularly in certain cancers, and suggest a potentially novel mechanism of oncogenesis through activation of a retrogene. (PMID:18835250)
• Pseudogene TDGF1P3 regulates the proliferation and metastasis of colorectal cancer cells via the miR-338-3p-PKM2 axis. (PMID:36436343)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cripto	ENSMUSG00000032494
rattus_norvegicus	Cripto	ENSRNOG00000037171

Paralogs (5): CFC1 (ENSG00000136698), CFC1B (ENSG00000152093), EGFL7 (ENSG00000172889), CRIPTO (ENSG00000241186), EGFL8 (ENSG00000241404)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:98658) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 49 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal mesoderm development	3
abnormal heart development	2
abnormal gastrulation	2
abnormal embryonic neuroepithelium morphology	2
abnormal rostral-caudal axis patterning	2
absent somites	2
absent notochord	1
abnormal germ layer development	1
absent mesoderm	1
abnormal endoderm development	1
failure of primitive streak formation	1
absent vitelline blood vessels	1
failure of embryo implantation	1
embryonic growth arrest	1
reduced female fertility	1
female infertility	1
decreased litter size	1
premature death	1
abnormal developmental patterning	1
abnormal embryonic tissue morphology	1
abnormal extraembryonic tissue morphology	1
abnormal primitive streak formation	1
abnormal chorion morphology	1
abnormal decidualization	1
abnormal uterine environment	1

+24 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	Q9I8Q3	59.1%	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
PAK3	protein-coding	5063
RTL9	protein-coding	57529
CHRDL1	protein-coding	91851
AMMECR1	protein-coding	9949
GNG5B	protein-coding	347687
SNORD96B	snoRNA	692226
MIR3978	ncRNA	100616491
TMEM164	protein-coding	84187

Protein

Protein identifiers

Protein CRIPTO3 — P51864 (reviewed: P51864)

Alternative names: Cripto, EGF-CFC family member 3, Cripto-3 growth factor, Epidermal growth factor-like cripto protein CR3, Teratocarcinoma-derived growth factor 1 pseudogene 3, Teratocarcinoma-derived growth factor 3

All UniProt accessions (1): P51864

UniProt curated annotations — full annotation on UniProt →

Function. Could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm. Activates the Nodal-dependent signaling pathway.

Subcellular location. Cell membrane.

Tissue specificity. Expressed weakly in lung, colon and breast. Expressed also strongly in primary cancer tissues; lung and colon cancers.

Similarity. Belongs to the EGF-CFC (Cripto-1/FRL1/Cryptic) family.

RefSeq proteins (1): NP_001384291* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR017047	Cripto	Family
IPR019011	Cryptic/Cripto_CFC-dom	Domain

Pfam: PF09443

UniProt features (9 total): disulfide bond 6, chain 1, domain 1, glycosylation site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51864-F1	66.63	0.31

Human Protein Atlas

Protein class: Predicted intracellular proteins, UniProt - Uncertain

Protein evidence: Evidence at transcript level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): 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.

Disulfide bonds (6)

Type	Positions
Disulfide bond	82–89, 83–95, 97–106, 115–133, 128–149, 131–140

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	79

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-1266738	Developmental Biology	—
R-HSA-1433617	Regulation of signaling by NODAL	electronic
R-HSA-1181150	Signaling by NODAL	electronic

MSigDB gene sets: 27 (showing top): GOCC_CELL_SURFACE, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_SPECIFICATION_OF_SYMMETRY, HOFMANN_MYELODYSPLASTIC_SYNDROM_RISK_DN, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION, GOBP_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY, GOMF_SIGNALING_RECEPTOR_BINDING, BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_UP, GOBP_CIRCULATORY_SYSTEM_DEVELOPMENT, GOMF_RECEPTOR_SERINE_THREONINE_KINASE_BINDING, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, chrXq23, GOBP_NODAL_SIGNALING_PATHWAY, REACTOME_REGULATION_OF_SIGNALING_BY_NODAL, GOBP_ENZYME_LINKED_RECEPTOR_PROTEIN_SIGNALING_PATHWAY

GO Biological Process (6): blood vessel development (GO:0001568), signal transduction (GO:0007165), determination of left/right symmetry (GO:0007368), heart development (GO:0007507), anterior/posterior pattern specification (GO:0009952), nodal signaling pathway (GO:0038092)

GO Molecular Function (3): growth factor activity (GO:0008083), nodal binding (GO:0038100), activin receptor binding (GO:0070697)

GO Cellular Component (3): extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Developmental Biology	1
Signaling by NODAL	1

GO top-level categories

19 GO namespaces:

Category	Terms
cellular anatomical structure	2
vasculature development	1
animal gross anatomical part developmental process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
determination of bilateral symmetry	1
left/right pattern formation	1
animal organ development	1
circulatory system development	1
regionalization	1
activin receptor signaling pathway	1
receptor ligand activity	1
protein binding	1
transmembrane receptor protein serine/threonine kinase binding	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
signal transduction	BP	direct assay
plasma membrane	CC	direct assay

Disease & clinical

Genetic variants

Variant evidence for CRIPTO3: 1 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

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

Disease associations

OMIM: gene `` | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST90002397_592	Mean spheric corpuscular volume	3e-28
GCST001612_10	Sex hormone-binding globulin levels	3e-16
GCST001612_14	Sex hormone-binding globulin levels	4e-14
GCST90011766_20	Glaucoma (primary open-angle)	4e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004696	sex hormone-binding globulin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression	1
Tretinoin	affects binding, increases reaction	1
Valproic Acid	decreases methylation	1

Clinical trials (associated diseases)

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