IRX4

Chr 5

iroquois homeobox 4

Also known as: IRXA3

NCBI Gene: 50805 ENSG00000113430 UniProt: P78413 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

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

3 unique Pathogenic / Likely Pathogenic· 93 VUS of 126 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 OE?0.37 (0.20–0.73)

0≤0.351.4

Missense OE?1.03 (0.94–1.14)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 6 / 16.1Missense obs/exp: 295 / 285.4Syn Z: -0.11

This gene — mechanism propensity

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

126 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS93

Likely Benign3

Benign26

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	1	3
Likely Pathogenic	0	0	0	0
VUS	92	0	1	93
Likely Benign	2	1	0	3
Benign	2	18	6	26
Total	98	19	8	125

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

View in ClinVar →

132 pathogenic / likely-pathogenic (of 145) ClinVar copy-number / structural variants overlap IRX4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →