IRX4

protein-coding

iroquois homeobox 4, the group of TALE class homeoboxes and pseudogenes

Gene summary

Predicted to enable DNA-binding transcription factor 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 transcription by RNA polymerase II. 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, Jun 2026]

MANE transcript

NM_016358.3

Inheritance

ClinVar variants

P:3U:94B:5

Top phenotype

Ventricular septal defect 1

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr5:1,877,413-1,887,236

External References & Databases

Ensembl (ENSG00000113430)

Transcript & Mutation Effects

hg38 • Region Span ~9.8 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: PanelApp Australia

ventricular septal defect 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013746

Submitter: Illumina

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*IRX4* was first reported in relation to autosomal dominant congenital heart disease in 2011 (Cheng et al., PMID: 21544582). Two variants (both missense) that have been reported in two probands with ventricular septal defect in one publication (PMID: 21544582) are included in this curation. The mechanism of pathogenicity is reported to be loss-of-function. No experimental evidence specific to congenital heart disease is available. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 12/11/2023 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRX4 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 91

not providedTotal: 9

Ventricular septal defect 1Total: 2

Tetralogy of FallotTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016358.3. 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		1 clinvar		2 clinvar	4
missense	2 clinvar		91 clinvar	2 clinvar	1 clinvar	96
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	3	0	94	2	3	102

Highest pathogenic variant AF is 0.000008217955

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016358.3	RefSeq	NP_057442.1	5	MANE Select
ENST00000231357.7	Ensembl	ENSP00000231357.2	5	MANE Select
NM_001278632.1	RefSeq	NP_001265561.1	5	Standard
NM_001278633.1	RefSeq	NP_001265562.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
irx4a	Danio rerio	Structure: presumptive cardiac ventricle heart tube Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

irx4a

Danio rerio

Structure: presumptive cardiac ventricle heart tube

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Heart Development
Cardiac Progenitor Differentiation

Biological Process

regulation of transcription by RNA polymerase II
heart development
establishment of animal organ orientation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000505790
Coding exons: 5
Length: 9810
Individuals with no LoFs: 125683
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125700
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.202	295	285	1.03	0.0000150	3201
Missense (PolyPhen)		61	85.176	0.71616		974
Synonymous	-0.108	140	138	1.01	0.00000803	1138
Loss of Function	2.34	6	16.1	0.372	6.89e-7	196

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.00011	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Likely to be an important mediator of ventricular differentiation during cardiac development.;

Recessive Scores

pRec: 0.119

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.790

Gene Damage Prediction

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