ZNF462

Chr 9AD

zinc finger protein 462

Also known as: WSKA, ZFPIP, Zfp462

NCBI Gene: 58499 ENSG00000148143 UniProt: Q96JM2 OMIM: 617371

This zinc finger transcription factor regulates chromatin structure and controls key developmental genes including SOX2, POU5F1/OCT4, and NANOG, while also regulating neuronal development and neural cell differentiation. Mutations cause Weiss-Kruszka syndrome, an autosomal dominant developmental disorder with intellectual disability, distinctive facial features, and growth abnormalities. The gene is extremely intolerant to loss-of-function variation (pLI >0.99, LOEUF 0.085), indicating that functional copies are critical for normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to C2H2-type zinc finger family of proteins. It contains multiple C2H2-type zinc fingers and may be involved in transcriptional regulation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.091 OMIM phenotype

Clinical Summary— ZNF462

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Gene-Disease Validity (ClinGen)

Weiss-Kruszka syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

85 unique Pathogenic / Likely Pathogenic· 463 VUS of 765 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ZNF462

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 8.56

OE 0.03 (0.01–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.35Z-score

OE missense 0.75 (0.71–0.79)

1058 obs / 1412.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.09)

0≤0.351.4

Missense OE?0.75 (0.71–0.79)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 3 / 91.2Missense obs/exp: 1058 / 1412.4Syn Z: -1.40

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongZNF462-related craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delayLOFAD

This gene — mechanism propensity

0.17100th %ile

GOF

0.1899th %ile

LOF

0.87top 5%

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

LOFprediction above median · 1 literature citation · 98% of P/LP variants are LoF · LOEUF 0.09 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHaploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28513610 ↗

ClinVar Variant Classifications

765 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56

Likely Pathogenic29

VUS463

Likely Benign165

Benign22

Conflicting11

Pathogenic

Likely Pathogenic

463

VUS

165

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	56	0	0	0	56
Likely Pathogenic	27	2	0	0	29
VUS	4	448	10	1	463
Likely Benign	0	77	3	85	165
Benign	0	8	4	10	22
Conflicting	—				11
Total	87	535	17	96	746

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap ZNF462 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →