IKZF2

Chr 2ADAR

IKAROS family zinc finger 2

Also known as: ANF1A2, HELIOS, ICHAD, IMDIA, ZNF1A2, ZNFN1A2

NCBI Gene: 22807 ENSG00000030419 UniProt: Q9UKS7 OMIM: 606234

This gene encodes Helios, a hematopoietic-specific zinc finger transcription factor that regulates lymphocyte development, particularly regulatory T cell function, and is required for outer hair cell maturation in the inner ear. Mutations cause autosomal dominant immunodeficiency with hearing loss and lymphoproliferation, typically presenting in early childhood. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the Ikaros family of zinc-finger proteins. Three members of this protein family (Ikaros, Aiolos and Helios) are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. This protein forms homo- or hetero-dimers with other Ikaros family members, and is thought to function predominantly in early hematopoietic development. Multiple transcript variants encoding different isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.292 OMIM phenotypes

Clinical Summary— IKZF2

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Gene-Disease Validity (ClinGen)

HELIOS deficiency · SDModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 67 VUS of 102 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.987

Z-score 3.95

OE 0.09 (0.04–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.40Z-score

OE missense 0.77 (0.69–0.86)

229 obs / 296.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.29)

0≤0.351.4

Missense OE?0.77 (0.69–0.86)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 2 / 22.0Missense obs/exp: 229 / 296.9Syn Z: -1.37

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedIKZF2-related ICHAD syndromeDNAD

This gene — mechanism propensity

0.4388th %ile

GOF

0.2994th %ile

LOF

0.79top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.29

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

102 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

VUS67

Likely Benign10

Benign10

Conflicting1

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	5	0	5
Likely Pathogenic	0	0	0	0	0
VUS	1	64	2	0	67
Likely Benign	0	4	0	6	10
Benign	0	1	7	2	10
Conflicting	—				1
Total	1	69	14	8	93

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap IKZF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →