IRX2

Chr 5

iroquois homeobox 2

Also known as: IRXA2

NCBI Gene: 153572 ENSG00000170561 UniProt: Q9BZI1 OMIM: 606198

The IRX2 protein is a transcription factor belonging to the Iroquois homeobox family that regulates gene expression during embryonic development and pattern formation. Mutations cause autosomal dominant microphthalmia with coloboma, corneal opacity, microcornea, and cataract, affecting ocular development. This gene shows low constraint against loss-of-function variants, suggesting tolerance to reduced gene dosage.

OMIM ResearchSummary from RefSeq

IRX2 is a member of the Iroquois homeobox gene family. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.[supplied by OMIM, Apr 2004]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.78

Clinical Summary— IRX2

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

74 VUS of 86 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?

0.78LOEUF

pLI 0.022

Z-score 2.14

OE 0.37 (0.19–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.56Z-score

OE missense 0.90 (0.81–1.01)

221 obs / 245.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.19–0.78)

0≤0.351.4

Missense OE?0.90 (0.81–1.01)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 5 / 13.5Missense obs/exp: 221 / 245.6Syn Z: -1.18

This gene — mechanism propensity

0.6551th %ile

GOF

0.3888th %ile

LOF

0.58top 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

86 submitted variants in ClinVar

ClinVar

Classification Summary

VUS74

Likely Benign4

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	74	0	74
Likely Benign	3	1	4
Benign	0	2	2
Total	77	3	80

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

View in ClinVar →

128 pathogenic / likely-pathogenic (of 135) ClinVar copy-number / structural variants overlap IRX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →