ZHX2

Chr 8

zinc fingers and homeoboxes 2

Also known as: AFR1, RAF

NCBI Gene: 22882 ENSG00000178764 UniProt: Q9Y6X8 OMIM: 609185

ZHX2 encodes a nuclear transcriptional repressor containing zinc fingers and homeobox DNA-binding domains that regulates gene expression during neural and retinal development, particularly promoting bipolar OFF-type cell differentiation in the retina and maintaining neural progenitor cells in the developing cortex. Mutations in ZHX2 cause neurodevelopmental disorders with autosomal dominant inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF = 0.518), suggesting some tolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, UniProt

The members of the zinc fingers and homeoboxes gene family are nuclear homodimeric transcriptional repressors that interact with the A subunit of nuclear factor-Y (NF-YA) and contain two C2H2-type zinc fingers and five homeobox DNA-binding domains. This gene encodes member 2 of this gene family. In addition to forming homodimers, this protein heterodimerizes with member 1 of the zinc fingers and homeoboxes family. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOEUF 0.52

Clinical Summary— ZHX2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

128 VUS of 148 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.034

Z-score 3.49

OE 0.29 (0.17–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.76Z-score

OE missense 0.90 (0.84–0.98)

452 obs / 499.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.17–0.52)

0≤0.351.4

Missense OE?0.90 (0.84–0.98)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 8 / 27.9Missense obs/exp: 452 / 499.7Syn Z: -1.51

ClinVar Variant Classifications

148 submitted variants in ClinVar

ClinVar

Classification Summary

VUS128

Likely Benign7

Benign5

128

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	128	0	128
Likely Benign	4	3	7
Benign	1	4	5
Total	133	7	140

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

View in ClinVar →

48 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap ZHX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →