IRX4

Chr 5

iroquois homeobox 4

Also known as: IRXA3

NCBI Gene: 50805ENSG00000113430UniProt: P78413OMIM: 606199

IRX4 encodes a transcription factor that regulates ventricular differentiation during cardiac development and is involved in neuron differentiation. Mutations cause autosomal dominant cardiac conduction defects and arrhythmias. The gene shows low constraint against loss-of-function variants (pLI 0.01, LOEUF 0.73), suggesting tolerance to haploinsufficiency in some contexts.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 0.73
Clinical Summary— IRX4
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
133 unique Pathogenic / Likely Pathogenic· 105 VUS of 269 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.73LOEUF
pLI 0.012
Z-score 2.34
OE 0.37 (0.20–0.73)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
-0.20Z-score
OE missense 1.03 (0.94–1.14)
295 obs / 285.4 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.37 (0.20–0.73)
0≤0.351.4
Missense OE1.03 (0.94–1.14)
0≤0.61.4
Synonymous OE1.01
0≤1.21.6
LoF obs/exp: 6 / 16.1Missense obs/exp: 295 / 285.4Syn Z: -0.11
DN
0.6743th %ile
GOF
0.4677th %ile
LOF
0.56top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

269 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic131
Likely Pathogenic2
VUS105
Likely Benign4
Benign26
131
Pathogenic
2
Likely Pathogenic
105
VUS
4
Likely Benign
26
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
128
1
131
Likely Pathogenic
0
0
2
0
2
VUS
0
92
12
1
105
Likely Benign
0
2
2
0
4
Benign
0
2
18
6
26
Total0981628268

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

View in ClinVar →

Protein Context — Lollipop Plot

IRX4 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
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
Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer.
Fernando A et al.·Genes (Basel)
2021
Unveiling the NEFH+ malignant cell subtype: Insights from single-cell RNA sequencing in prostate cancer progression and tumor microenvironment interactions.
Wang J et al.·Front Immunol
2024
Ischemia challenged epicardial adipose tissue stem cells-derived extracellular vesicles alter the gene expression of cardiac fibroblasts to cardiomyocyte like phenotype.
Thankam FG et al.·Transl Res
2023
Expression Profile and Prognostic Values of IRX Family Members in Lung Adenocarcinoma.
Zhang J et al.·Curr Med Chem
2025
Evaluation of IRX Genes and Conserved Noncoding Elements in a Region on 5p13.3 Linked to Families with Familial Idiopathic Scoliosis and Kyphosis.
Justice CM et al.·G3 (Bethesda)
2016
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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