IRX1

Chr 5

iroquois homeobox 1

Also known as: IRX-5, IRXA1

NCBI Gene: 79192 ENSG00000170549 UniProt: P78414 OMIM: 606197

This gene encodes an Iroquois homeobox transcription factor that regulates embryonic pattern formation. Mutations cause autosomal dominant developmental delay, intellectual disability, and multiple congenital anomalies affecting craniofacial features, limbs, and other organ systems. The gene shows low constraint against loss-of-function variants, consistent with the dominant inheritance pattern observed in affected families.

OMIM ResearchSummary from RefSeq

This gene encodes a member of the Iroquois homeobox protein family. Homeobox genes in this family are involved in pattern formation in the embryo. The gene product has been identified as a tumor suppressor in gastric (PMID: 21602894, 20440264) and head and neck cancers (PMID: 18559491). A pseudogene of this gene is located on chromosome 13. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.07

Clinical Summary— IRX1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

80 VUS of 99 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?

1.07LOEUF

pLI 0.000

Z-score 1.40

OE 0.57 (0.32–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.59Z-score

OE missense 1.11 (1.00–1.23)

266 obs / 240.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.57 (0.32–1.07)

0≤0.351.4

Missense OE?1.11 (1.00–1.23)

0≤0.61.4

Synonymous OE?1.43

0≤1.21.6

LoF obs/exp: 7 / 12.3Missense obs/exp: 266 / 240.2Syn Z: -3.62

This gene — mechanism propensity

0.6649th %ile

GOF

0.4678th %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

99 submitted variants in ClinVar

ClinVar

Classification Summary

VUS80

Likely Benign8

Benign6

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	80	0	80
Likely Benign	0	8	8
Benign	1	5	6
Total	81	13	94

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

View in ClinVar →

128 pathogenic / likely-pathogenic (of 132) ClinVar copy-number / structural variants overlap IRX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →