IRX4

Chr 5

iroquois homeobox 4

Also known as: IRXA3

NCBI Gene: 50805ENSG00000113430UniProt: P78413

Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell development; neuron differentiation; and regulation of DNA-templated transcription. Predicted to act upstream of or within heart development. Predicted to be located in chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2025]

266
ClinVar variants
132
Pathogenic / LP
0.01
pLI score
0
Active trials
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
132 Pathogenic / Likely Pathogenic· 104 VUS of 266 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

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

Typical tolerance to LoF variation

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 1.03 (0.94–1.14)
295 obs / 285.4 exp
Tolerant

Tolerant to missense variation

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.0.37 (0.20–0.73)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.03 (0.94–1.14)
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.1.01
0≤1.21.6
LoF obs/exp: 6 / 16.1Missense obs/exp: 295 / 285.4Syn Z: -0.11

ClinVar Variant Classifications

266 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic130
Likely Pathogenic2
VUS104
Likely Benign4
Benign26
130
Pathogenic
2
Likely Pathogenic
104
VUS
4
Likely Benign
26
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
127
1
130
Likely Pathogenic
0
0
2
0
2
VUS
0
91
12
1
104
Likely Benign
0
2
2
0
4
Benign
0
2
18
6
26
Total0971618266

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
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
Genomic imbalances in syndromic congenital heart disease.
Molck MC et al.·J Pediatr (Rio J)
2017
Genetic linkage studies of a North Carolina macular dystrophy family.
Audere M et al.·Medicina (Kaunas)
2016
A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus.
Spisak S et al.·Nat Commun
2023Functional
HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas.
Kostareli E et al.·J Clin Invest
2013
Functional analysis of novel genetic variants of NKX2-5 associated with nonsyndromic congenital heart disease.
Dixit R et al.·Am J Med Genet A
2021Functional
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
Altered histone mark deposition and DNA methylation at homeobox genes in human oral squamous cell carcinoma.
Marcinkiewicz KM et al.·J Cell Physiol
2014
Whole exome sequencing with a focus on cardiac disease-associated genes in families of sudden unexplained deaths in Yunnan, southwest of China.
Wei SJ et al.·BMC Genomics
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools