ZFHX2

protein-coding

zinc finger homeobox 2, the group of Zinc fingers C2H2-type|ZF class homeoboxes and pseudogenes

Gene summary

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in regulation of sensory perception of pain. Located in nucleus. Implicated in Marsili syndrome. [provided by Alliance of Genome Resources, Jul 2025]

Previous symbols:

ZNF409

MANE transcript

NM_033400.3

Inheritance

ClinVar variants

P:1U:466B:155

Top phenotype

Marsili syndrome

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr14:23,520,857-23,556,192

External References & Databases

Ensembl (ENSG00000136367)

Transcript & Mutation Effects

hg38 • Region Span ~35.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

indifference to pain, congenital, autosomal dominantLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007828

Submitter: Illumina

indifference to pain, congenital, autosomal dominantLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007828

Submitter: Ambry Genetics

indifference to pain, congenital, autosomal dominantLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007828

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Marsili syndromeAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Insensitivity to pain can result in injuries

Refs: 29253101

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZFHX2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 536

not providedTotal: 96

ZFHX2-related disorderTotal: 43

Indifference to pain, congenital, autosomal dominantTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033400.3. 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	92 clinvar	4 clinvar	98
missense	1 clinvar		460 clinvar	50 clinvar	9 clinvar	520
nonsense			1 clinvar			1
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)						0
Total	1	0	466	142	13	622

Highest pathogenic variant AF is 0.0000021673732

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033400.3	RefSeq	NP_207646.2	9	MANE Select
ENST00000419474.5	Ensembl	ENSP00000413418.2	9	MANE Select
ENST00000412565.2	Ensembl	ENSP00000409464.2	1	Standard
ENST00000555334.1	Ensembl	ENSP00000451342.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
adult behavior
positive regulation of transcription, DNA-templated
regulation of sensory perception of pain

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
zinc ion binding
transcription regulatory region DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000419474
Coding exons: 9
Length: 35336
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.95	983	1.28e+3	0.768	0.0000713	16267
Missense (PolyPhen)		315	474.42	0.66397		5894
Synonymous	3.65	412	518	0.796	0.0000281	5582
Loss of Function	6.07	10	61.3	0.163	0.00000322	850

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in transcriptional regulation.;

Recessive Scores

pRec: 0.0969

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.192

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High