ZNF462

Chr 9AD

zinc finger protein 462

Also known as: WSKA, ZFPIP, Zfp462

NCBI Gene: 58499 ENSG00000148143 UniProt: Q96JM2

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]

Primary Disease Associations & Inheritance

Weiss-Kruszka syndromeMIM #618619

Active trials

Pathogenic / LP

381

ClinVar variants

Pubs (1 yr)

3.4

Missense Z· constrained

0.09

LOEUF· LoF intolerant

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

34 Pathogenic / Likely Pathogenic· 283 VUS of 381 total submissions

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Clinical Trials

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

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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?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.09)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.71–0.79)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08

0≤1.21.6

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

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 · 68% of P/LP variants are LoF · LOEUF 0.09

Literature Evidence

LOFHaploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay.PMID:28513610

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