CFC1

Summary

CFC1 (cryptic, EGF-CFC family member 1, HGNC:18292) is a protein-coding gene on chromosome 2q21.1, encoding Cryptic protein (P0CG37). NODAL coreceptor involved in the correct establishment of the left-right axis.

This gene encodes a member of the epidermal growth factor (EGF)- Cripto, Frl-1, and Cryptic (CFC) family, which are involved in signalling during embryonic development. Proteins in this family share a variant EGF-like motif, a conserved cysteine-rich domain, and a C-terminal hydrophobic region. The protein encoded by this gene is necessary for patterning the left-right embryonic axis. Mutations in this gene are associated with defects in organ development, including autosomal visceral heterotaxy and congenital heart disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 55997 — RefSeq curated summary.

At a glance

• Gene–disease (curated): heterotaxy, visceral, 2, autosomal (Strong, GenCC)
• Clinical variants (ClinVar): 50 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 17
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_032545

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18292
Approved symbol	CFC1
Name	cryptic, EGF-CFC family member 1
Location	2q21.1
Locus type	gene with protein product
Status	Approved
Aliases	CRYPTIC
Ensembl gene	ENSG00000136698
Ensembl biotype	protein_coding
OMIM	605194
Entrez	55997

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000259216, ENST00000615342, ENST00000621673

RefSeq mRNA: 3 — MANE Select: NM_032545 NM_001270420, NM_001270421, NM_032545

CCDS: CCDS2162, CCDS74573, CCDS74574

Canonical transcript exons

ENST00000259216 — 6 exons

Exon	Start	End
ENSE00002443349	130598642	130598815
ENSE00002443947	130597494	130597603
ENSE00002460996	130592165	130593076
ENSE00002507922	130598910	130598959
ENSE00002536274	130597868	130597982
ENSE00003899514	130599265	130599575

Expression profiles

Bgee: expression breadth broad, 76 present calls, max score 98.06.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	98.06	gold quality
pituitary gland	UBERON:0000007	89.10	gold quality
adenohypophysis	UBERON:0002196	88.25	gold quality
pancreas	UBERON:0001264	85.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.96	gold quality
hypothalamus	UBERON:0001898	83.30	gold quality
body of pancreas	UBERON:0001150	80.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.00	gold quality
nucleus accumbens	UBERON:0001882	74.56	gold quality
primary visual cortex	UBERON:0002436	74.05	gold quality
cerebellum	UBERON:0002037	73.17	gold quality
cerebellar cortex	UBERON:0002129	73.08	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.08	gold quality
cerebellar hemisphere	UBERON:0002245	73.04	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.16	gold quality
putamen	UBERON:0001874	70.68	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	70.14	gold quality
substantia nigra	UBERON:0002038	70.11	gold quality
brain	UBERON:0000955	69.91	gold quality
right frontal lobe	UBERON:0002810	69.09	gold quality
temporal lobe	UBERON:0001871	66.54	gold quality
amygdala	UBERON:0001876	66.40	gold quality
anterior cingulate cortex	UBERON:0009835	65.76	gold quality
frontal cortex	UBERON:0001870	65.50	gold quality
cerebral cortex	UBERON:0000956	65.32	gold quality
caudate nucleus	UBERON:0001873	65.26	gold quality
fundus of stomach	UBERON:0001160	64.97	gold quality
right uterine tube	UBERON:0001302	63.85	gold quality
body of stomach	UBERON:0001161	63.03	gold quality
prefrontal cortex	UBERON:0000451	62.99	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-31	yes	3533.37
E-MTAB-5061	yes	3425.04
E-MTAB-9388	yes	1916.40
E-MTAB-9154	yes	1456.19
E-HCAD-56	yes	756.26
E-GEOD-81547	yes	29.78
E-GEOD-83139	yes	10.24
E-MTAB-8271	yes	7.18
E-ANND-3	yes	4.83
E-ENAD-27	no	7.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, FLI1, GATA3, HIF1A, KDM5B, KMT2A, MYC, PURB, TCF3, TFAP2A, TP63, YBX1

miRNA regulators (miRDB)

22 targeting CFC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-4662A-5P	98.48	67.18	1007
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-192-3P	97.52	67.66	1001
HSA-MIR-8056	97.15	64.49	769
HSA-MIR-103B	95.51	66.85	441

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle (PMID:11799476)
• results suggest that heterozygous cryptic family 1 (CFC1) mutation may represent a genetic predisposition to biliary atresia splenic malformation syndrome (PMID:18162845)
• Characterization of the glycosylphosphatidylinositol-anchor signal sequence of human Cryptic with a hydrophilic extension is reported. (PMID:18930707)
• CFC1 may be involved in the etiology of non-syndromic congenital heart disease in a Chinese population. (PMID:19853937)
• Data indicate that the duplication and deletion of CFC1 protein may play key roles in the occurrence of heterotaxy syndrome. (PMID:25423076)
• enhances macrophage phagocytic activity and upregulates the production of anti- and pro-inflammatory cytokines via the NF-kappaB signaling pathway (PMID:26476731)
• Results demonstrated that over expression of Snail suppresses Cryptic expression and confirmed that Snail directly binds to Cryptic gene promoter and regulates its expression. (PMID:27793090)
• The knockdown and overexpression of CFC1 were performed using a lentiviral system in NB cell lines. The overexpression of CFC1 increased sphere formation, cell growth, and colony formation. (PMID:28620148)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cfc1	ENSMUSG00000026124
rattus_norvegicus	Cfc1	ENSRNOG00000042646

Paralogs (5): CFC1B (ENSG00000152093), EGFL7 (ENSG00000172889), CRIPTO3 (ENSG00000225366), CRIPTO (ENSG00000241186), EGFL8 (ENSG00000241404)

Protein

Protein identifiers

Cryptic protein — P0CG37 (reviewed: P0CG37)

Alternative names: Cryptic family protein 1

All UniProt accessions (3): A0A087WWV2, A0A087WX98, P0CG37

UniProt curated annotations — full annotation on UniProt →

Function. NODAL coreceptor involved in the correct establishment of the left-right axis. May play a role in mesoderm and/or neural patterning during gastrulation.

Subcellular location. Cell membrane. Secreted.

Post-translational modifications. N-glycosylated.

Disease relevance. Heterotaxy, visceral, 2, autosomal (HTX2) [MIM:605376] A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can be associated with a variety of congenital defects including cardiac malformations. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (3): NP_001257349, NP_001257350, NP_115934* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF09443

UniProt features (14 total): sequence variant 3, disulfide bond 3, mutagenesis site 2, signal peptide 1, chain 1, propeptide 1, domain 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0CG37-F1	64.18	0.24

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 (1): 158

Disulfide bonds (3): 90–97, 91–103, 105–114

Glycosylation sites (1): 52

Mutagenesis-validated functional residues (2):

Position	Phenotype
191–223	does not affect the cellular localization and the biological activity.
191–223	increased nodal dependent signaling.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-1433617	Regulation of signaling by NODAL

MSigDB gene sets: 87 (showing top): GOCC_CELL_SURFACE, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION, GOBP_GASTRULATION, GOBP_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY, GOBP_EMBRYO_DEVELOPMENT, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_CIRCULATORY_SYSTEM_DEVELOPMENT, GOCC_SIDE_OF_MEMBRANE, GOBP_EMBRYONIC_MORPHOGENESIS, GOMF_RECEPTOR_SERINE_THREONINE_KINASE_BINDING, GSE13762_CTRL_VS_125_VITAMIND_DAY12_DC_UP, MOREAUX_MULTIPLE_MYELOMA_BY_TACI_UP, GOBP_NODAL_SIGNALING_PATHWAY, WNT_UP.V1_UP

GO Biological Process (7): blood vessel development (GO:0001568), determination of left/right symmetry (GO:0007368), gastrulation (GO:0007369), heart development (GO:0007507), anterior/posterior pattern specification (GO:0009952), nodal signaling pathway (GO:0038092), signal transduction (GO:0007165)

GO Molecular Function (2): nodal binding (GO:0038100), activin receptor binding (GO:0070697)

GO Cellular Component (5): extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986), side of membrane (GO:0098552), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Developmental Biology	1
Signaling by NODAL	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
membrane	2
vasculature development	1
anatomical structure development	1
determination of bilateral symmetry	1
left/right pattern formation	1
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
embryonic morphogenesis	1
animal organ development	1
circulatory system development	1
regionalization	1
activin receptor signaling pathway	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein binding	1
transmembrane receptor protein serine/threonine kinase binding	1
cell periphery	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

794 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFC1	NODAL	Q96S42	920
CFC1	ACVR2B	Q13705	917
CFC1	FMNL1	O95466	905
CFC1	ZIC3	O60481	897
CFC1	LEFTY2	O00292	873
CFC1	GDF1	P27539	861
CFC1	MED13L	Q71F56	847
CFC1	ACVR1B	P36896	789
CFC1	NKX2-6	A6NCS4	779
CFC1	LEFTY1	O75610	741
CFC1	GPR31	O00270	719
CFC1	FOXH1	O75593	671
CFC1	INVS	Q9Y283	629
CFC1	PITX2	Q99697	611
CFC1	CRELD1	Q96HD1	607

IntAct

2 interactions, top by confidence:

A	B	Type	Score
CFC1	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (126): UBR4 (Affinity Capture-MS), CHRD (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), BMP4 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), CNTNAP3B (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), SEPN1 (Affinity Capture-MS), CERCAM (Affinity Capture-MS), SEZ6L2 (Affinity Capture-MS), RDH11 (Affinity Capture-MS), PLAU (Affinity Capture-MS), ART5 (Affinity Capture-MS)

ESM2 similar proteins: A2A699, A2ALI5, A2AWH2, A2BD09, A2BDP1, A4IFM1, A4IHZ3, A6QLD2, A6QPA0, A8MVW0, B0BN44, B1AL88, F1N4E5, O14525, O15105, O35144, O35253, O75129, O75949, O88406, O94983, P0C7U0, P0CG37, P51693, Q03157, Q29016, Q2F7Z7, Q3T0Q2, Q3UPI1, Q4W8E7, Q5EGE1, Q5PQX1, Q61137, Q68BL7, Q68BL8, Q6H9L7, Q6UWH4, Q766D5, Q76KP1, Q80Z10

Diamond homologs: P0CG36, P0CG37, P13385, P51864, P51865, P97766, Q9I8Q3, O88277, Q5F226, A0A2K5V015, Q5R6R1, Q5T1H1, O97507, Q20911

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	23
Likely benign	9
Benign	11

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
5187	NM_032545.4(CFC1):c.334C>T (p.Arg112Cys)	Pathogenic
5190	NM_032545.4(CFC1):c.361_362+18dup	Pathogenic
4294348	NM_032545.4(CFC1):c.195dup (p.Glu66fs)	Likely pathogenic

SpliceAI

757 predictions. Top by Δscore:

Variant	Effect	Δscore
2:130597863:CCCA:C	donor_loss	1.0000
2:130597864:CCA:C	donor_loss	1.0000
2:130597865:CACC:C	donor_loss	1.0000
2:130597866:ACCT:A	donor_loss	1.0000
2:130597867:CCTGC:C	donor_loss	1.0000
2:130598635:AACTT:A	donor_loss	1.0000
2:130598636:ACTTA:A	donor_loss	1.0000
2:130598637:CTT:C	donor_loss	1.0000
2:130598638:TTA:T	donor_loss	1.0000
2:130598639:T:TG	donor_loss	1.0000
2:130598640:A:AC	donor_gain	1.0000
2:130598640:AC:A	donor_gain	1.0000
2:130598641:C:CC	donor_gain	1.0000
2:130598641:CC:C	donor_gain	1.0000
2:130598641:CCCT:C	donor_gain	1.0000
2:130598812:TAGC:T	acceptor_gain	1.0000
2:130598814:GC:G	acceptor_gain	1.0000
2:130598814:GCC:G	acceptor_loss	1.0000
2:130598815:CCT:C	acceptor_gain	1.0000
2:130598816:C:CC	acceptor_gain	1.0000
2:130598816:C:T	acceptor_gain	1.0000
2:130598816:CTTTA:C	acceptor_loss	1.0000
2:130598817:T:C	acceptor_gain	1.0000
2:130598818:T:TC	acceptor_gain	1.0000
2:130598908:A:AC	donor_gain	1.0000
2:130598909:C:CC	donor_gain	1.0000
2:130599259:CCTTA:C	donor_loss	1.0000
2:130599260:CTTA:C	donor_loss	1.0000
2:130599262:TAC:T	donor_loss	1.0000
2:130599263:ACC:A	donor_loss	1.0000

AlphaMissense

1435 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:130597573:C:A	W131C	0.996
2:130597573:C:G	W131C	0.996
2:130597904:A:C	F109C	0.993
2:130597924:G:C	F102L	0.993
2:130597924:G:T	F102L	0.993
2:130597925:A:C	F102C	0.993
2:130597926:A:G	F102L	0.993
2:130597903:G:C	F109L	0.992
2:130597903:G:T	F109L	0.992
2:130597905:A:G	F109L	0.992
2:130597889:C:T	C114Y	0.988
2:130597889:C:G	C114S	0.985
2:130597890:A:T	C114S	0.985
2:130597899:C:A	G111C	0.985
2:130597889:C:A	C114F	0.981
2:130597922:C:T	C103Y	0.980
2:130597888:G:C	C114W	0.979
2:130597904:A:G	F109S	0.979
2:130597575:A:G	W131R	0.977
2:130597575:A:T	W131R	0.977
2:130597916:C:G	C105S	0.972
2:130597917:A:T	C105S	0.972
2:130597952:T:A	N93I	0.972
2:130597916:C:T	C105Y	0.971
2:130597537:G:C	F143L	0.970
2:130597537:G:T	F143L	0.970
2:130597539:A:G	F143L	0.970
2:130597898:C:A	G111V	0.970
2:130597917:A:G	C105R	0.970
2:130597922:C:G	C103S	0.970

dbSNP variants (sampled 300 via entrez): RS1001670176 (2:130600258 G>C), RS1002225608 (2:130597970 C>G,T), RS1005760575 (2:130591673 A>G), RS1006629045 (2:130591940 T>C,G), RS1006794992 (2:130595566 C>G,T), RS1006927902 (2:130594377 G>A,T), RS1013330462 (2:130597059 G>A), RS1014409754 (2:130596056 T>C), RS1015531595 (2:130591696 C>T), RS1017150861 (2:130598219 C>G), RS1017387685 (2:130596360 C>A,G), RS1022062826 (2:130594378 G>A), RS1022429108 (2:130592081 A>G), RS1024499014 (2:130597086 C>A,T), RS1024578928 (2:130596068 T>G)

Disease associations

OMIM: gene MIM:605194 | disease phenotypes: MIM:605376

GenCC curated gene-disease

Disease	Classification	Inheritance
heterotaxy, visceral, 2, autosomal	Strong	Autosomal dominant

Mondo (1): heterotaxy, visceral, 2, autosomal (MONDO:0011546)

Orphanet (1): Visceral heterotaxy (Orphanet:450)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0001274	Agenesis of corpus callosum
HP:0001651	Dextrocardia
HP:0001669	Transposition of the great arteries
HP:0001696	Situs inversus totalis
HP:0001719	Double outlet right ventricle
HP:0001746	Asplenia
HP:0001748	Polysplenia
HP:0002566	Intestinal malrotation
HP:0003363	Abdominal situs inversus
HP:0003577	Congenital onset
HP:0003829	Typified by incomplete penetrance
HP:0006695	Atrioventricular canal defect
HP:0011537	Left atrial isomerism
HP:0011599	Mesocardia
HP:0033379	Bilateral superior vena cava

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
MT19c compound	decreases expression	1
Arsenic	affects expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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