GeneBe

NODAL

protein-coding

nodal growth differentiation factor, the group of Transforming growth factor beta superfamily

Gene summary

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. [provided by RefSeq, Aug 2016]

MANE transcript

NM_018055.5

Inheritance

AD

ClinVar variants

P:19U:96B:47

Top phenotype

Heterotaxy, visceral, 5, autosomal

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr10:70,431,936-70,447,951

External References & Databases

Ensembl (ENSG00000156574)NCBI Gene (4838)OMIM (601265)HGNC:7865GenCCUniProt (Q96S42)AlphaFoldClinVar (NODAL)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~16.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

heterotaxy, visceral, 5, autosomalDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700112

Submitter: G2P

congenital heart disease with heterotaxy syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1060197

Submitter: ClinGen

*NODAL* was first reported in relation to autosomal dominant congenital heart disease with heterotaxy syndrome in 1997 (Gebbia et al., PMID: 9354794). This gene has been associated with isolated congenital heart disease and heterotaxy, visceral, 5, autosomal. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern and phenotypic variability. Therefore, the two entities have been lumped into one disease entity. At least 12 unique variants (missense, nonsense, frameshift, splice site) have been reported in 14 probands in seven publications (PMID: 19064609, 19553149, 19933292, 30293987, 34328347, 34666056, 38605286). The mechanism of pathogenicity appears to be loss-of-function. Some variants were inherited from healthy parents showing approximately 50% penetrance (PMID: 38605286). This gene-disease relationship is supported by biochemical function data showing that NODAL is a crucial signaling molecule belonging to the transforming growth factor-β (TGF-β) superfamily, and animal models recapitulating the disease phenotype (PMID: 17287255, 12231623, 30446628). In summary, there is definitive evidence to support the relationship between the *NODAL* gene and autosomal dominant congenital heart disease with heterotaxy syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date August 5th, 2025 (SOP Version 11).

heterotaxy, visceral, 5, autosomalSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700112

Submitter: Labcorp Genetics (formerly Invitae)

heterotaxy, visceral, 5, autosomalMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700112

Submitter: PanelApp Australia

heterotaxy, visceral, 5, autosomalMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700112

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Heterotaxy, visceral, 5, autosomalAD

Manifestation: Cardiovascular; Gastrointestinal; Pulmonary; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management; Cardiac transplantation has been described

Comments: The condition can involve multiple congenital anomalies; Cardiac transplantation has been described

Refs: 19064609Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NODAL variants in ClinVar

12 Conditions Cataloged
Heterotaxy, visceral, 5, autosomalTotal: 107
not providedTotal: 43
Inborn genetic diseasesTotal: 37
Holoprosencephaly sequenceTotal: 23
NODAL-related disorderTotal: 20
not specifiedTotal: 12
Abnormal heart morphologyTotal: 3
Visceral heterotaxyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018055.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
6
clinvar
30
clinvar
3
clinvar
 39
missense
2
clinvar
83
clinvar
12
clinvar
2
clinvar
 99
nonsense
3
clinvar
2
clinvar
2
clinvar
 7
start loss
1
clinvar
 1
frameshift
2
clinvar
6
clinvar
4
clinvar
 12
splice donor/acceptor (+/-2bp)
3
clinvar
1
clinvar
 4
Total51496425162

Highest pathogenic variant AF is 0.000012997248

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_018055.5RefSeqNP_060525.33MANE Select
ENST00000287139.8EnsemblENSP00000287139.33MANE Select
NM_001329906.2RefSeqNP_001316835.12Standard
ENST00000414871.1EnsemblENSP00000394468.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
ndr1Danio rerio

Structure: hatching gland cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • TGF-beta signaling pathway - Homo sapiens (human)
  • Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
  • TGF-Core
  • Cardiac Progenitor Differentiation
  • Differentiation Pathway

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • trophectodermal cellular morphogenesis
  • neural fold formation
  • liver development
  • placenta development

Molecular Function

  • cytokine activity
  • transforming growth factor beta receptor binding
  • growth factor activity
  • morphogen activity
  • type I activin receptor binding

Cellular Component

  • extracellular space

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000287139
Coding exons
3
Length
15637
Individuals with no LoFs
125742
Homozygous LoFs
0
Heterozygous LoFs
6
Defined
125748
p
0.0000239
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.9711561940.8040.00001142239
Missense (PolyPhen)5778.9630.72186958
Synonymous1.316883.20.8170.00000474707
Loss of Function3.39115.30.06548.26e-7146

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000260.000026rare
South Asian00.0absent
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Essential for mesoderm formation and axial patterning during embryonic development. {ECO:0000250}.;
Disease
DISEASE: Heterotaxy, visceral, 5, autosomal (HTX5) [MIM:270100]: 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 been associated with 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. {ECO:0000269|PubMed:19064609, ECO:0000269|PubMed:9354794}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.426

Intolerance Scores

LoFtool
0.272
RVIS EVS
-0.29
RVIS percentile EVS
32.94

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.834

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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