NODAL

Summary

NODAL (nodal growth differentiation factor, HGNC:7865) is a protein-coding gene on chromosome 10q22.1, encoding Nodal homolog (Q96S42). Essential for mesoderm formation and axial patterning during embryonic development.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which regulates early embryonic development. This protein is required for maintenance of human embryonic stem cell pluripotency and may play a role in human placental development. Mutations in this gene are associated with heterotaxy, a condition characterized by random orientation of visceral organs with respect to the left-right axis.

Source: NCBI Gene 4838 — RefSeq curated summary.

At a glance

• Gene–disease (curated): heterotaxy, visceral, 5, autosomal (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 186 total — 6 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 144
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_018055

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7865
Approved symbol	NODAL
Name	nodal growth differentiation factor
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000156574
Ensembl biotype	protein_coding
OMIM	601265
Entrez	4838

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000287139, ENST00000414871

RefSeq mRNA: 2 — MANE Select: NM_018055 NM_001329906, NM_018055

CCDS: CCDS7304

Canonical transcript exons

ENST00000287139 — 3 exons

Exon	Start	End
ENSE00001027224	70441475	70441681
ENSE00001027226	70435286	70435983
ENSE00001260007	70431936	70433088

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 86.26.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6689 / max 151.2230, expressed in 118 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109843	1.5600	116
109842	0.1089	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	86.26	gold quality
cardiac muscle of right atrium	UBERON:0003379	82.00	gold quality
left ventricle myocardium	UBERON:0006566	81.73	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.45	gold quality
sperm	CL:0000019	76.37	silver quality
epithelium of nasopharynx	UBERON:0001951	74.97	gold quality
tibialis anterior	UBERON:0001385	74.13	silver quality
epithelium of mammary gland	UBERON:0003244	73.52	gold quality
mammary duct	UBERON:0001765	73.42	gold quality
myocardium	UBERON:0002349	72.00	gold quality
oocyte	CL:0000023	71.70	silver quality
kidney epithelium	UBERON:0004819	71.39	gold quality
gastrocnemius	UBERON:0001388	70.82	gold quality
muscle of leg	UBERON:0001383	69.57	gold quality
epithelial cell of pancreas	CL:0000083	68.57	gold quality
esophagus squamous epithelium	UBERON:0006920	67.70	gold quality
ileal mucosa	UBERON:0000331	67.28	silver quality
nasal cavity epithelium	UBERON:0005384	67.25	gold quality
buccal mucosa cell	CL:0002336	67.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.51	gold quality
mucosa of stomach	UBERON:0001199	66.22	gold quality
pancreatic ductal cell	CL:0002079	64.37	silver quality
oral cavity	UBERON:0000167	64.02	gold quality
hindlimb stylopod muscle	UBERON:0004252	63.53	gold quality
secondary oocyte	CL:0000655	63.13	silver quality
pigmented layer of retina	UBERON:0001782	62.94	silver quality
deltoid	UBERON:0001476	62.70	silver quality
amniotic fluid	UBERON:0000173	61.82	gold quality
parotid gland	UBERON:0001831	61.64	gold quality
decidua	UBERON:0002450	61.53	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-109979	yes	416.23
E-MTAB-3929	yes	350.50
E-MTAB-7008	no	361.49
E-ANND-3	no	1.63

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
LIF	Activation
MMP2	Activation
TDGF1	Activation

Upstream regulators (CollecTRI, top): DLL1, FOXD3, FOXH1, NANOG, SIX3, SMAD2, TGIF1, ZNF362

miRNA regulators (miRDB)

42 targeting NODAL, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-6877-3P	98.98	65.83	560
HSA-MIR-6819-3P	98.95	65.57	572
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-1178-3P	98.57	67.09	890
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-1199-5P	98.44	66.51	829
HSA-MIR-6751-3P	98.44	66.35	835
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-4456	97.50	64.88	1678

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• mRNA expression of Nodal, a ligand for ALK7, was detected in placentae of different gestational age (PMID:12606401)
• the Nodal-ALK7 pathway inhibits cell proliferation by inducing G(1) cell cycle arrest (PMID:15150278)
• Nicalin/Nodal modulator complex antagonizes Nodal signaling during mesendodermal patterning in zebrafish (PMID:15257293)
• Smad2/3 is activated in undifferentiated human embryonic stem cells and required for the expression of genes controlling Nodal signaling (PMID:15308665)
• We propose that an abnormal Nodal-Pitx2c pathway represents a unifying mechanism for the cardiovascular malformations observed in Cited2(-/-) mice, and that such malformations may be the sole manifestation of a laterality defect. (PMID:15475956)
• Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. (PMID:15501227)
• These results demonstrate for a functional role for TGF-beta ligands in regulation of mammalian Mixl1, identify FoxH1 as an essential co-activator, and implicate Nodal as the embryonic regulator of Mixl1 in mesendoderm morphogenesis. (PMID:15982639)
• Data show that the Activin/Nodal pathway maintains pluripotency through mechanism(s) in which FGF acts as a competence factor, suggesting distinct mechanisms for preservation of pluripotency in mouse and human ESCs. (PMID:16179608)
• REVIEW: Nodal (and its signaling partners) present unique targets for both immunologic and pharmacologic therapies in metastatic melanoma. (PMID:17373879)
• GPI attachment of CR-1 is required for the paracrine activity as a Nodal co-receptor. (PMID:17925387)
• These results show that inhibition of Nodal signaling promotes neuronal specification, indicating a role for this pathway in controlling early neural development of pluripotent cells. (PMID:18022151)
• Cripto facilitates Nodal signaling and inhibits activin signaling by forming receptor complexes with these ligands that are structurally and functionally similar. (PMID:18089557)
• Together, these findings show that TGFbeta superfamily activation of Smad2/3 is required for repression of spontaneous differentiation under strain. (PMID:18234825)
• Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to heart defects and holoprosencephaly. (PMID:18538293)
• the trophoblast induction effect of BMP4 correlates with and depends on the inhibition of Activin/Nodal signaling (PMID:18596037)
• Mutations in NODAL is a cause for sporadic human cardiovascular malformations. (PMID:19064609)
• Nanog in turn prevents neuroectoderm differentiation induced by FGF signalling and limits the transcriptional activity of the Smad2/3 cascade, blocking progression along the endoderm lineage (PMID:19279133)
• Activin A, activin receptor type II, nodal, and cripto mRNA are expressed by eutopic and ectopic endometrium in women with ovarian endometriosis. (PMID:19386982)
• A mutational analysis of the human NODAL gene in a large panel of patients with phenotypes compatible with diminished NODAL ligand function, is described. (PMID:19553149)
• The expression of Nodal in normal and malignant endometrial cells that lack Lefty strongly supports an important role for this embryonic morphogen in the tissue remodelling events that occur across the menstrual cycle and in tumourogenesis. (PMID:19874624)
• Nodal may regulate glioma progression through the induction of the leukemia inhibitory factor (LIF) and Cripto-1. (PMID:20383200)
• Nodal gene expression is associated with formation of VM-like structures in a physiologically relevant model of human melanoma tumorigenesis (PMID:20482672)
• The low expression of Nodal in normal and dysplastic nevi, and its increasing expression with the progression of malignant lesions, are suggestive of a role for Nodal in melanoma progression. (PMID:20495543)
• molecular model of activin receptor-like kinase 4/Cripto/Nodal complex built by homology modeling as well as docking tests aimed at identifying potential binding epitopes (PMID:20629020)
• This study revealed that alteration of Nodal expression in glioma cells resulted in changes to VEGF secretion, and subsequent colony formation, in vivo tumor growth, and angiogenesis. (PMID:21116837)
• Study identifies an important role for cross talk between Notch4 and Nodal in metastatic melanoma, placing Notch4 upstream of Nodal. (PMID:21159651)
• These findings suggest that the Nodal/ALK7 pathway plays important roles in human placentation and that its abnormal signaling may contribute to the development of preeclampsia. (PMID:21356369)
• These findings showed that Nodal signaling promotes cyclin G2 transcription by upregulating FoxO3a expression, inhibiting FoxO3a phosphorylation and enhancing its synergistic interaction with Smads. (PMID:21532621)
• Activin-Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors (PMID:21630377)
• An aberrant nodal signaling pathway is re-expressed and functionally active in prostate cancer cells. (PMID:21656830)
• Nodal transcriptional network that governs endoderm formation, was elucidated (PMID:21741376)
• The role of Nodal in melanoma progression may be less prominent and immunotherapeutic targeting of Nodal could be potentially harmful. (PMID:22002671)
• Low oxygen levels induce the expression of the embryonic morphogen Nodal. (PMID:22031289)
• This is the first study to suggest that novel mutations of NODAL may be involved in the etiology of nonsyndromic congenital heart disease in a Chinese population. (PMID:22352765)
• show that three major stem cell pluripotency/differentiation pathways, Notch, canonical Wnt, and transforming growth factor-beta, are affected by smoke exposure, and that Nodal signaling through SMAD2 is impacted by effects on Lefty1, Nodal, and FoxH1 (PMID:22381624)
• Overexpressing Nodal reverses the effect of miR-378a-5p on cell invasion. (PMID:22454525)
• Lefty A may account for the tumor suppressive activity of human liver stem cells as a result of an inhibition of the Nodal-signalling pathway . (PMID:22469982)
• we discuss certain characteristics related to Nodal expression and function and how these can facilitate acquisition and interpretation of expression data, contributing to our understanding of the potential role of Nodal in human cancer[human] (PMID:22508696)
• results indicate that the expression of Nodal is associated with advanced stage, invasive breast cance; data suggest a potential role for Nodal as biomarker for disease progression and promising target for anti-Nodal therapy in breast cancer (PMID:22577960)
• Nodal is a potential target for the treatment of breast cancer angiogenesis and progression. (PMID:22855743)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nodal	ENSMUSG00000037171
rattus_norvegicus	Nodal	ENSRNOG00000000556
drosophila_melanogaster	myo	FBGN0026199
drosophila_melanogaster	daw	FBGN0031461
drosophila_melanogaster	mav	FBGN0039914
caenorhabditis_elegans		WBGENE00000936
caenorhabditis_elegans		WBGENE00006852

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), TGFB1 (ENSG00000105329), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF5 (ENSG00000125965), GDF1 (ENSG00000130283), BMP15 (ENSG00000130385), GDF15 (ENSG00000130513), GDF11 (ENSG00000135414), MSTN (ENSG00000138379), INHBE (ENSG00000139269), LEFTY2 (ENSG00000143768), GDF7 (ENSG00000143869), BMP3 (ENSG00000152785), BMP6 (ENSG00000153162), GDF6 (ENSG00000156466), INHBB (ENSG00000163083), BMP10 (ENSG00000163217), GDF9 (ENSG00000164404), INHBC (ENSG00000175189), BMP8A (ENSG00000183682), GDF3 (ENSG00000184344), LEFTY1 (ENSG00000243709), GDF2 (ENSG00000263761), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Nodal homolog — Q96S42 (reviewed: Q96S42)

All UniProt accessions (2): Q96S42, H7C0E4

UniProt curated annotations — full annotation on UniProt →

Function. Essential for mesoderm formation and axial patterning during embryonic development.

Subunit / interactions. Homodimer; disulfide-linked.

Subcellular location. Secreted.

Disease relevance. Heterotaxy, visceral, 5, autosomal (HTX5) [MIM:270100] An autosomal dominant 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. HTX5 clinical features include situs inversus viscerum or situs ambiguus, congenital heart defect, transposition of the great vessels ventricular septal defect, atrial septal defect, truncus communis, and dextrocardia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (2): NP_001316835, NP_060525* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001839	TGF-b_C	Domain
IPR015615	TGF-beta-like	Family
IPR017948	TGFb_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019

UniProt features (24 total): sequence variant 7, disulfide bond 4, turn 3, strand 3, helix 2, glycosylation site 2, signal peptide 1, propeptide 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4N1D	X-RAY DIFFRACTION	1.91

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96S42-F1	75.81	0.35

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 (4): 247–313, 276–344, 280–346, 312

Glycosylation sites (2): 72, 199

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: 535 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_PRIMITIVE_STREAK_FORMATION

GO Biological Process (73): negative regulation of transcription by RNA polymerase II (GO:0000122), trophectodermal cellular morphogenesis (GO:0001831), neural fold formation (GO:0001842), liver development (GO:0001889), placenta development (GO:0001890), embryonic placenta development (GO:0001892), maternal placenta development (GO:0001893), vasculature development (GO:0001944), heart looping (GO:0001947), inhibition of neuroepithelial cell differentiation (GO:0002085), determination of left/right asymmetry in lateral mesoderm (GO:0003140), cell surface receptor protein serine/threonine kinase signaling pathway (GO:0007178), transforming growth factor beta receptor signaling pathway (GO:0007179), germ cell development (GO:0007281), brain development (GO:0007420), cell population proliferation (GO:0008283), embryonic pattern specification (GO:0009880), polarity specification of proximal/distal axis (GO:0010085), regulation of gastrulation (GO:0010470), positive regulation of vascular endothelial growth factor production (GO:0010575), negative regulation of cell development (GO:0010721), positive regulation of cell-cell adhesion (GO:0022409), floor plate morphogenesis (GO:0033505), somatic stem cell population maintenance (GO:0035019), endodermal cell differentiation (GO:0035987), nodal signaling pathway (GO:0038092), cell migration involved in gastrulation (GO:0042074), positive regulation of angiogenesis (GO:0045766), positive regulation of transcription by RNA polymerase II (GO:0045944), axial mesodermal cell fate specification (GO:0048327), mesendoderm development (GO:0048382), digestive tract morphogenesis (GO:0048546), embryonic cranial skeleton morphogenesis (GO:0048701), formation of anatomical boundary (GO:0048859), positive regulation of epithelial cell proliferation (GO:0050679), embryonic process involved in female pregnancy (GO:0060136), maternal process involved in parturition (GO:0060137), positive regulation of SMAD protein signal transduction (GO:0060391), left lung morphogenesis (GO:0060460), negative regulation of androgen receptor signaling pathway (GO:0060766)

GO Molecular Function (6): cytokine activity (GO:0005125), growth factor activity (GO:0008083), morphogen activity (GO:0016015), type I activin receptor binding (GO:0070698), protein binding (GO:0005515), receptor ligand activity (GO:0048018)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

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
receptor ligand activity	3
animal organ development	2
placenta development	2
developmental process involved in reproduction	2
regulation of anatomical structure morphogenesis	2
regulation of embryonic development	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cell morphogenesis	1
trophectodermal cell differentiation	1
embryonic morphogenesis	1
primary neural tube formation	1
morphogenesis of embryonic epithelium	1
anatomical structure formation involved in morphogenesis	1
morphogenesis of an epithelial fold	1
gland development	1
hepaticobiliary system development	1
in utero embryonic development	1
embryonic organ development	1
anatomical structure development	1
maternal process involved in female pregnancy	1
system development	1
circulatory system development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
negative regulation of epithelial cell differentiation	1
regulation of timing of cell differentiation	1
neuroepithelial cell differentiation	1
determination of left/right symmetry	1
lateral mesoderm development	1
enzyme-linked receptor protein signaling pathway	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
central nervous system development	1
head development	1
cellular process	1

Protein interactions and networks

STRING

1076 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NODAL	CRIPTO	P13385	963
NODAL	ZIC3	O60481	923
NODAL	CFC1	P0CG37	920
NODAL	ACVR2B	Q13705	905
NODAL	LEFTY1	O75610	877
NODAL	LEFTY2	O00292	868
NODAL	ACVR1B	P36896	802
NODAL	ACVR2A	P27037	781
NODAL	GPR31	O00270	760
NODAL	SMAD2	Q15796	751
NODAL	FOXH1	O75593	716
NODAL	TGFBR1	P36897	691
NODAL	ACVR1C	Q8NER5	664
NODAL	SIX3	O95343	617
NODAL	CER1	O95813	612

IntAct

9 interactions, top by confidence:

A	B	Type	Score
KRTAP6-3	NODAL	psi-mi:“MI:0915”(physical association)	0.560
KRT31	NODAL	psi-mi:“MI:0915”(physical association)	0.560
NODAL	RSPRY1	psi-mi:“MI:0915”(physical association)	0.400
NODAL	TXNDC5	psi-mi:“MI:0915”(physical association)	0.400
NODAL	KRT31	psi-mi:“MI:0915”(physical association)	0.000
NODAL	KRTAP6-3	psi-mi:“MI:0915”(physical association)	0.000
KRTAP6-3	NODAL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): RSPRY1 (Affinity Capture-MS), NODAL (Reconstituted Complex), NODAL (Reconstituted Complex), NODAL (Reconstituted Complex), NODAL (Reconstituted Complex), NODAL (Two-hybrid), KRTAP6-3 (Two-hybrid), TXNDC5 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTW7, A0A1D5NSK0, A0A1L8HYT7, A0A286YEC0, G7PWZ3, O77755, O88959, P0C0K7, P17490, P23276, P43021, P51882, P59509, P59996, P70505, Q02853, Q04912, Q04962, Q04997, Q0V8J4, Q0VAY3, Q17R55, Q3U435, Q499S5, Q4R7Z5, Q58Y75, Q62190, Q6MG64, Q76MJ5, Q7TN88, Q7Z442, Q80W65, Q8BMN4, Q8CJH3, Q8IVN8, Q8VCS0, Q91X21, Q96KR4, Q96PQ0, Q96S42

Diamond homologs: A8E7N9, G5EEL5, O08717, O18828, O18830, O19006, O42222, O46564, O46576, O88959, O95390, O95393, O95972, P03970, P07713, P07995, P08476, P09534, P12643, P12644, P12645, P18075, P18331, P20722, P20863, P21274, P21275, P22003, P22004, P22444, P23359, P25703, P27092, P27539, P30884, P30885, P30886, P34820, P34821, P34822

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
NODAL	up-regulates	Apoptosis
NODAL	down-regulates	Proliferation
NODAL	“up-regulates activity”	ACVR1C	binding
TDGF1	“up-regulates activity”	NODAL	binding
NODAL	“up-regulates activity”	ACVR1B	binding
NODAL	“up-regulates quantity by expression”	MMP2	“transcriptional regulation”
NODAL	“up-regulates quantity by expression”	LIF	“transcriptional regulation”
NODAL	“up-regulates quantity by expression”	TDGF1	“transcriptional regulation”
NODAL	up-regulates	Cell_death

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	9
Uncertain significance	102
Likely benign	36
Benign	17

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1069992	NM_018055.5(NODAL):c.555del (p.Thr186fs)	Pathogenic
3338700	NM_018055.5(NODAL):c.110C>A (p.Ser37Ter)	Pathogenic
3340587	NM_018055.5(NODAL):c.317_318dup (p.Gly107fs)	Pathogenic
545545	NM_018055.5(NODAL):c.397C>T (p.Gln133Ter)	Pathogenic
663619	NM_018055.5(NODAL):c.446del (p.Gly149fs)	Pathogenic
986360	NM_018055.5(NODAL):c.591C>A (p.Tyr197Ter)	Pathogenic
1805542	NM_018055.5(NODAL):c.158_165del (p.Pro53fs)	Likely pathogenic
2584455	NM_018055.5(NODAL):c.253C>T (p.Gln85Ter)	Likely pathogenic
3255023	NM_018055.5(NODAL):c.735del (p.Gln245fs)	Likely pathogenic
3366958	NM_018055.5(NODAL):c.408dup (p.Phe137fs)	Likely pathogenic
423103	NM_018055.5(NODAL):c.824G>A (p.Arg275His)	Likely pathogenic
4293741	NM_018055.5(NODAL):c.709C>T (p.Arg237Ter)	Likely pathogenic
545543	NM_018055.5(NODAL):c.700_707del (p.Arg234fs)	Likely pathogenic
545544	NM_018055.5(NODAL):c.194-1G>T	Likely pathogenic
571254	NM_018055.5(NODAL):c.891+2T>A	Likely pathogenic

SpliceAI

837 predictions. Top by Δscore:

Variant	Effect	Δscore
10:70433084:AGACT:A	acceptor_gain	1.0000
10:70433085:GACT:G	acceptor_gain	1.0000
10:70433087:CT:C	acceptor_gain	1.0000
10:70433088:TC:T	acceptor_loss	1.0000
10:70433089:C:CC	acceptor_gain	1.0000
10:70433089:C:T	acceptor_loss	1.0000
10:70433090:T:C	acceptor_loss	1.0000
10:70441471:CTACC:C	donor_loss	1.0000
10:70441472:TACC:T	donor_loss	1.0000
10:70441474:CCTT:C	donor_gain	1.0000
10:70435280:TCCCA:T	donor_loss	0.9900
10:70435281:CCCA:C	donor_loss	0.9900
10:70435282:CCACC:C	donor_loss	0.9900
10:70435283:CA:C	donor_loss	0.9900
10:70435285:C:CT	donor_loss	0.9900
10:70435981:CAT:C	acceptor_gain	0.9900
10:70441470:CCTA:C	donor_loss	0.9900
10:70441473:A:AC	donor_gain	0.9900
10:70441474:C:CC	donor_gain	0.9900
10:70433086:ACT:A	acceptor_gain	0.9800
10:70433087:CTC:C	acceptor_gain	0.9800
10:70433088:TCT:T	acceptor_gain	0.9800
10:70435286:C:G	donor_loss	0.9800
10:70435983:TC:T	acceptor_loss	0.9800
10:70435984:C:CA	acceptor_loss	0.9800
10:70435984:C:CC	acceptor_gain	0.9800
10:70435985:T:C	acceptor_loss	0.9800
10:70441400:C:A	donor_gain	0.9800
10:70441469:GCCTA:G	donor_loss	0.9800
10:70433089:C:A	acceptor_gain	0.9700

AlphaMissense

2258 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:70435350:C:G	C276S	0.999
10:70435351:A:T	C276S	0.999
10:70435375:G:A	P268S	0.999
10:70435409:G:C	F256L	0.999
10:70435409:G:T	F256L	0.999
10:70435411:A:G	F256L	0.999
10:70433042:C:G	C313S	0.998
10:70433042:C:T	C313Y	0.998
10:70433043:A:T	C313S	0.998
10:70435338:C:G	C280S	0.998
10:70435339:A:G	C280R	0.998
10:70435339:A:T	C280S	0.998
10:70435345:C:A	G278C	0.998
10:70435350:C:T	C276Y	0.998
10:70435351:A:G	C276R	0.998
10:70435353:C:G	R275P	0.998
10:70435374:G:T	P268H	0.998
10:70435375:G:T	P268T	0.998
10:70435394:C:A	W261C	0.998
10:70435394:C:G	W261C	0.998
10:70435410:A:C	F256C	0.998
10:70435437:C:G	C247S	0.998
10:70435438:A:T	C247S	0.998
10:70432944:A:G	C346R	0.997
10:70432963:C:A	M339I	0.997
10:70432963:C:G	M339I	0.997
10:70432963:C:T	M339I	0.997
10:70433041:A:C	C313W	0.997
10:70433043:A:G	C313R	0.997
10:70435349:A:C	C276W	0.997

dbSNP variants (sampled 300 via entrez): RS1000060478 (10:70438708 G>A), RS1000078881 (10:70432246 A>C,G), RS1000606770 (10:70439350 T>A,G), RS1000772283 (10:70432646 C>T), RS1000799131 (10:70445875 G>A,C), RS1000956803 (10:70439675 A>G), RS1001082886 (10:70433607 G>A,T), RS1001135220 (10:70433302 G>A), RS1001471220 (10:70439868 C>A,T), RS1001624352 (10:70436653 G>A), RS1001955304 (10:70432060 A>G), RS1002069636 (10:70442719 A>G), RS1002111880 (10:70438882 T>C), RS1002519244 (10:70437164 C>T), RS1002545136 (10:70443246 G>A)

Disease associations

OMIM: gene MIM:601265 | disease phenotypes: MIM:270100, MIM:236100, MIM:306955, MIM:613061, MIM:194200

GenCC curated gene-disease

Disease	Classification	Inheritance
heterotaxy, visceral, 5, autosomal	Definitive	Autosomal dominant
situs inversus	Supportive	Autosomal dominant

Mondo (7): heterotaxy, visceral, 5, autosomal (MONDO:0700112), situs inversus (MONDO:0010029), holoprosencephaly (MONDO:0016296), visceral heterotaxy (MONDO:0018677), basal cell carcinoma, susceptibility to, 4 (MONDO:0013104), congenitally corrected transposition of the great arteries (MONDO:0016301), Wolff-Parkinson-White syndrome (MONDO:0008685)

Orphanet (6): Visceral heterotaxy (Orphanet:450), Situs inversus totalis (Orphanet:101063), Holoprosencephaly (Orphanet:2162), Congenitally corrected transposition of the great arteries (Orphanet:216694), Situs ambiguus (Orphanet:157769), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

144 total (30 of 144 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000062	Ambiguous genitalia
HP:0000071	Ureteral stenosis
HP:0000073	Ureteral duplication
HP:0000089	Renal hypoplasia
HP:0000104	Renal agenesis
HP:0000119	Abnormality of the genitourinary system
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000322	Short philtrum
HP:0000407	Sensorineural hearing impairment
HP:0000446	Narrow nasal bridge
HP:0000453	Choanal atresia
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000601	Hypotelorism
HP:0000612	Iris coloboma
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000736	Short attention span
HP:0000737	Irritability
HP:0000739	Anxiety

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000080041	Congenitally Corrected Transposition of the Great Arteries	C14.240.400.915.150; C14.280.400.915.150; C16.131.240.400.915.150
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380
D012857	Situs Inversus	C16.131.810
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression	2
Tretinoin	affects expression, affects cotreatment, decreases reaction, increases expression	2
Valproic Acid	affects expression	2
fluorene-9-bisphenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenite	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
monoisoamyl-2,3-dimercaptosuccinate	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases reaction, increases expression	1
Chir 99021	affects cotreatment, decreases reaction, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Ethanol	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	increases expression, increases response to substance	1
Dactinomycin	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Teratogens	increases expression	1
Carboplatin	increases response to substance	1
Asbestos, Crocidolite	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT00005016	Not specified	COMPLETED	Study of the Experiences and Needs of Parents Continuing a Pregnancy Following a Prenatal Diagnosis of Holopresencephaly
NCT00088426	Not specified	COMPLETED	Clinical and Genetic Studies on Holoprosencephaly
NCT00645645	Not specified	COMPLETED	A Study of the Genetic Analysis of Brain Disorders
NCT04691414	Not specified	COMPLETED	Retrospective Study Using Next Generation Sequencing (NGS) on Biological Samples to Improve Genetic Counseling for Patients With Previously Explored Craniofacial Midline Defects.
NCT01591928	Not specified	COMPLETED	Heterotaxy Syndrome and Intestinal Rotation Abnormalities - A Prospective Study
NCT01929967	Not specified	COMPLETED	Defining Immunodeficiency in Heterotaxy Syndrome: Pilot Study Data
NCT02432079	Not specified	RECRUITING	Molecular Genetics of Heterotaxy and Related Congenital Heart Defects
NCT04788082	Not specified	WITHDRAWN	Clinical Impact of Rapid Prototyping 3D Models for Surgical Management
NCT05524324	Not specified	RECRUITING	Cardiac Resynchronization Therapy in Adult Congenital Heart Disease With Systemic Right Ventricle: RIGHT-CRT
NCT06932081	Not specified	RECRUITING	Adult Congenital Heart Disease International EValuation of the Effectiveness of SGLT2i Registry
NCT00251121	Not specified	COMPLETED	Routine Mini-invasive Electrophysiology Study for Patients Feeling Tachycardia, With a Negative Holter ECG
NCT00873470	Not specified	TERMINATED	Wolff-Parkinson-White Syndrome Anterograde Refractory Period of Accessory Duct
NCT03207373	Not specified	TERMINATED	Stress ECG Test for the Evaluation of the Risk of Sudden Cardiac Death in a Paediatric Cohort With WPW Pattern
NCT03301935	Not specified	COMPLETED	Risk Assessment in Patients With Symptomatic- and Asymptomatic Preexcitation
NCT03816033	Not specified	UNKNOWN	Cryotherapy Versus Radiofrequency Catheter Ablation Research Program
NCT04106622	Not specified	UNKNOWN	Accessory Pathway Antegrade Effective Refractory Period Among WPW Patients: the Risk in Relation to the Location
NCT06349109	Not specified	COMPLETED	Physical Activity in Children With Wolff-Parkinson-White Syndrome
NCT07435181	Not specified	NOT_YET_RECRUITING	Comparative Outcomes of Radiofrequency Ablation of Concealed and Manifest Accessory Pathways: a Single Center, Retrospective Observational Study