NFATC1

protein-coding

nuclear factor of activated T cells 1, the group of Nuclear factors of activated T-cells |IPT domain containing

Gene summary

The product of this gene is a component of the nuclear factor of activated T cells DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation, and an inducible nuclear component. Proteins belonging to this family of transcription factors play a central role in inducible gene transcription during immune response. The product of this gene is an inducible nuclear component. It functions as a major molecular target for the immunosuppressive drugs such as cyclosporin A. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Different isoforms of this protein may regulate inducible expression of different cytokine genes. [provided by RefSeq, Jul 2013]

MANE transcript

NM_001278669.2

Inheritance

AD, AR

ClinVar variants

U:227B:125

Top phenotype

NFATC1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.25

Max pathogenic AF

—

Genomic locus

chr18:79,395,856-79,529,325

External References & Databases

Ensembl (ENSG00000131196)

Transcript & Mutation Effects

hg38 • Region Span ~133.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*NFATC1* was first reported in relation to autosomal dominant congenital heart disease in 2012 (Abdul-Sater et al., PMID:23226213). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Bicuspid aortic valve, tricuspid atresia, atrioventricular septal defect, congenital heart disease, tetralogy of Fallot, and ventricular septal defect. At least fifteen unique variants (missense and nonsense) have been reported in fifteen probands in seven publications (PMIDs: 23226213, 34363434, 25260786, 30007050, 34426522, 32859249, 37406974). However, only two variants were scorable since most of the missense variants had a high minor allele frequency (> 0.00001) in gnomAD v4.1.0 and very low REVEL scores. All of the experimental evidence was performed with these missense variants, and therefore was not scored (PMIDs: 30007050, 23226213, 34363434). In summary, there is limited evidence supporting the relationship between *NFATC1* and autosomal dominant congenital heart disease. Although more human genetic evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Congenital Heart Disease GCEP on July 17, 2023 (SOP Version 9). It was re-evaluated on June 2, 2026 (SOP Version 12). As a result of this reevaluation, the classification increased from Disputed to Limited with the addition of new genetic evidence (PMID: 37406974)

inborn error of immunityMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0003778

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NFATC1 variants in ClinVar

3 Conditions Cataloged

not providedTotal: 203

not specifiedTotal: 192

NFATC1-related disorderTotal: 42

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001278669.2. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	71 clinvar	20 clinvar	92
missense			218 clinvar	29 clinvar	5 clinvar	252
nonsense			4 clinvar			4
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	227	100	25	352

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001278669.2	RefSeq	NP_001265598.1	10	MANE Select
ENST00000427363.7	Ensembl	ENSP00000389377.2	10	MANE Select
NM_001278670.2	RefSeq	NP_001265599.1	9	Standard
NM_001278672.2	RefSeq	NP_001265601.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxytocin signaling pathway - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
B cell receptor signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)

Biological Process

cytokine production
transcription by RNA polymerase II
Wnt signaling pathway, calcium modulating pathway
negative regulation of Wnt signaling pathway
calcineurin-NFAT signaling cascade

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II transcription factor binding
RNA polymerase II transcription coactivator binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
transcription factor complex
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000329101
Coding exons: 10
Length: 133470
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125747
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.735	590	642	0.918	0.0000462	5928
Missense (PolyPhen)		177	240.06	0.73732		2188
Synonymous	-1.45	353	320	1.10	0.0000268	2003
Loss of Function	3.96	8	32.3	0.248	0.00000163	356

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000057	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00016	0.00014	rare
South Asian	0.000066	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 or IL-4 gene transcription. Also controls gene expression in embryonic cardiac cells. Could regulate not only the activation and proliferation but also the differentiation and programmed death of T-lymphocytes as well as lymphoid and non-lymphoid cells (PubMed:10358178). Required for osteoclastogenesis and regulates many genes important for osteoclast differentiation and function (By similarity). {ECO:0000250|UniProtKB:O88942, ECO:0000269|PubMed:10358178}.;

Recessive Scores

pRec: 0.659

Intolerance Scores

LoFtool: 0.322
RVIS EVS: -1.85
RVIS percentile EVS: 2.05

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.768

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium