ZNF423

Chr 16ADAR

zinc finger protein 423

Also known as: Ebfaz, JBTS19, NPHP14, OAZ, Roaz, ZFP423, Zfp104, hOAZ

NCBI Gene: 23090 ENSG00000102935 UniProt: Q2M1K9

The protein encoded by this gene is a nuclear protein that belongs to the family of Kruppel-like C2H2 zinc finger proteins. It functions as a DNA-binding transcription factor by using distinct zinc fingers in different signaling pathways. Thus, it is thought that this gene may have multiple roles in signal transduction during development. Mutations in this gene are associated with nephronophthisis-14 and Joubert syndrome-19. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2012]

Primary Disease Associations & Inheritance

Joubert syndrome 19MIM #614844

ADAR

Nephronophthisis 14MIM #614844

ADAR

Active trials

Pathogenic / LP

494

ClinVar variants

Pubs (1 yr)

2.5

Missense Z

0.19

LOEUF· LoF intolerant

Clinical Summary— ZNF423

🧬

Gene-Disease Validity (ClinGen)

ciliopathy · ARModerate

Moderate evidence — consider for supplementary testing

⚡

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.

📋

ClinVar Variants

5 Pathogenic / Likely Pathogenic· 234 VUS of 494 total submissions

📖

GeneReview available — ZNF423

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

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.

0.19LOEUF

pLI 1.000

Z-score 5.54

OE 0.07 (0.03–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.

2.49Z-score

OE missense 0.76 (0.71–0.81)

625 obs / 826.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.07 (0.03–0.19)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.71–0.81)

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.1.07

0≤1.21.6

LoF obs/exp: 3 / 41.6Missense obs/exp: 625 / 826.5Syn Z: -1.12

0.2399th %ile

GOF

0.2696th %ile

LOF

0.82top 5%

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

LOFprediction above median · LOEUF 0.19

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