NKX2-5

Chr 5AD

NK2 homeobox 5

Also known as: CHNG5, CSX, CSX1, HLHS2, NKX2.5, NKX2E, NKX4-1, VSD3

NCBI Gene: 1482ENSG00000183072UniProt: P52952

This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

Atrial septal defect 7, with or without AV conduction defectsMIM #108900
AD
Conotruncal heart malformations, variableMIM #217095
Hypoplastic left heart syndrome 2MIM #614435
AD
Hypothyroidism, congenital nongoitrous, 5MIM #225250
AD
Tetralogy of FallotMIM #187500
AD
Ventricular septal defect 3MIM #614432
AD
0
Active trials
91
Pathogenic / LP
436
ClinVar variants
5
Pubs (1 yr)
0.2
Missense Z
0.33
LOEUF· LoF intolerant
Clinical Summary— NKX2-5
🧬
Gene-Disease Validity (ClinGen)
NKX2.5-related congenital, conduction and myopathic heart disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
91 Pathogenic / Likely Pathogenic· 215 VUS of 436 total submissions
📖
GeneReview available — NKX2-5
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.33LOEUF
pLI 0.945
Z-score 2.81
OE 0.00 (0.00–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.20Z-score
OE missense 0.96 (0.85–1.09)
178 obs / 185.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.85–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 0 / 9.2Missense obs/exp: 178 / 185.6Syn Z: -0.02
DN
0.4586th %ile
GOF
0.2696th %ile
LOF
0.81top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 48% of P/LP variants are LoF · LOEUF 0.33
DN1 literature citation
GOF1 literature citation

Literature Evidence

DNNKX2-5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominPMID:16418214
GOFOur study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease.PMID:26146939
LOFTwo are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding.PMID:9651244

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

436 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic71
Likely Pathogenic20
VUS215
Likely Benign103
Benign12
Conflicting15
71
Pathogenic
20
Likely Pathogenic
215
VUS
103
Likely Benign
12
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
34
10
27
0
71
Likely Pathogenic
10
6
4
0
20
VUS
0
196
18
1
215
Likely Benign
0
7
15
81
103
Benign
0
0
11
1
12
Conflicting
—15
Total442197583436

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NKX2-5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NKX2-5-related dilated cardiomyopathy

limited
ADUndeterminedUncertain
Cardiac
G2P ↗

NKX2-5-related congenital hypothyroidism non-goitrous

definitive
ADDominant NegativeAltered Gene Product Structure
Dev. Disorders
G2P ↗

NKX2-5-related tetralogy of Fallot

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

NKX2-5-related atrial septal defect with atrioventricular conduction defects

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A novel NKX2-5 mutation causing atrial septal defect and high-degree atrioventricular block in a Chinese family.
Liu H et al.·ESC Heart Fail
2026
NKX2-5 Mutation and ICD Implantation in a Pregnant AV Block Patient.
Alhmouz MM et al.·JACC Case Rep
2025Open Access
Case Report: The nonsense variation of the cardiac transcription factor NKX2-5 has been identified in a Chinese family with nonsyndromic congenital heart disease.
Zhang H et al.·Front Genet
2025Open AccessCase report
NKX2-5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation.
Li X et al.·Adv Sci (Weinh)
2025Open Access
Identification of a novel NKX2-5 variant in a young Ecuadorian patient with atrioventricular block and bradycardia: a case report.
Ruiz-Pozo VA et al.·Front Cardiovasc Med
2025Open AccessCase report
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients