IKZF2

protein-coding

IKAROS family zinc finger 2, the group of Zinc fingers C2H2-type

Gene summary

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]

Previous symbols:

ZNFN1A2

MANE transcript

NM_001387220.1

Inheritance

AD, AR, SD

ClinVar variants

P:1U:76B:14

Top phenotype

ICHAD syndrome

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr2:212,999,691-213,152,427

External References & Databases

Ensembl (ENSG00000030419)

Transcript & Mutation Effects

hg38 • Region Span ~152.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005365

Submitter: Ambry Genetics

immunodeficiency diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0021094

Submitter: Ambry Genetics

immunodysregulation with variable immunodeficiency and autoimmunityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0800139

Submitter: Ambry Genetics

ICHAD syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0979234

Submitter: PanelApp Australia

immunodysregulation with variable immunodeficiency and autoimmunityMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0800139

Submitter: ClinGen

The IKZF2 gene encodes the transcription factor HELIOS. Helios is a member of the Ikaros family; as a transcription factor, it can bind DNA in essential regions to control hematopoiesis, cell cycle, apoptosis, and cell function of immune cells. HELIOS deficiency (MONDO:0800139) has a wide range of phenotypes: lymphadenopathy, hypogammaglobulinemia, recurrent infections, and immune dysregulation with incomplete penetrance. A total of seven variants, including nonsense and missense, have been reported in 10 patients in 3 publications only (PMID: 34826260, 34826259, 34920454). All variants except for one were found in an autosomal dominant trait, for that reason the model of inheritance used for this curation was autosomal dominant. Experimental evidence includes a reduction of HELIOS expression in the patient´s cells (Lymphocytes, NK cells), loss of the dimerization ability and DNA binding activity, and disruption of the protein-protein interaction and transcriptional activity. Additionally, the HELIOS knockout mouse recapitulates most of the cellular phenotypes and the development of autoimmunity seen in patients with HELIOS deficiency. A recuration was conducted on March 11 of 2025, with the review of new evidence seen in patients with IKZF2-ICHAD (Immunedysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay ) phenotype. However, the experts agreed to split the IKZF2-ICHAD phenotype. In summary, there is moderate evidence to support this gene-disease relationship.

nonsyndromic genetic hearing lossSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: PanelApp Australia

immunodysregulation with variable immunodeficiency and autoimmunitySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0979233

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IKZF2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 75

not providedTotal: 14

IKZF2-related conditionTotal: 9

ICHAD syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001387220.1. 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			2 clinvar	8 clinvar	1 clinvar	11
missense		1 clinvar	70 clinvar	4 clinvar	1 clinvar	76
nonsense						0
start loss			1 clinvar			1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	1	76	12	2	91

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001387220.1	RefSeq	NP_001374149.1	7	MANE Select
ENST00000434687.6	Ensembl	ENSP00000412869.1	7	MANE Select
NM_001079526.2	RefSeq	NP_001072994.1	7	Standard
NM_001371274.1	RefSeq	NP_001358203.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

biological_process
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
molecular_function
DNA-binding transcription factor activity
protein binding
protein homodimerization activity

Cellular Component

nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000457361
Coding exons: 7
Length: 152723
Individuals with no LoFs: 125612
Homozygous LoFs: 2
Heterozygous LoFs: 132
Defined: 125746
p: 0.000533

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.40	229	297	0.771	0.0000155	3549
Missense (PolyPhen)		64	113.98	0.56152		1419
Synonymous	-1.37	120	102	1.17	0.00000544	931
Loss of Function	3.95	2	22.0	0.0909	0.00000126	272

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.0058	0.0057	notable
European (Non-Finnish)	0.000054	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Associates with Ikaros at centromeric heterochromatin.;

Recessive Scores

pRec: 0.171

Intolerance Scores

LoFtool: 0.515
RVIS EVS: 0.02
RVIS percentile EVS: 55.61

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.922

Gene Damage Prediction

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