NEK8

Chr 17ADAR

NIMA related kinase 8

Also known as: JCK, NEK12A, NPHP9, PKD8, RHPD2

NCBI Gene: 284086 ENSG00000160602 UniProt: Q86SG6

This gene encodes a member of the serine/threionine protein kinase family related to NIMA (never in mitosis, gene A) of Aspergillus nidulans. The encoded protein may play a role in cell cycle progression from G2 to M phase. Mutations in the related mouse gene are associated with a disease phenotype that closely parallels the juvenile autosomal recessive form of polycystic kidney disease in humans. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Nephronophthisis 9MIM #613824

Polycystic kidney disease 8MIM #620903

Renal-hepatic-pancreatic dysplasia 2MIM #615415

Active trials

Pathogenic / LP

190

ClinVar variants

Pubs (1 yr)

1.1

Missense Z

0.80

LOEUF

Clinical Summary— NEK8

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Gene-Disease Validity (ClinGen)

renal-hepatic-pancreatic dysplasia 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

12 Pathogenic / Likely Pathogenic· 111 VUS of 190 total submissions

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GeneReview available — NEK8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

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.

0.80LOEUF

pLI 0.000

Z-score 2.50

OE 0.54 (0.38–0.80)

Tolerant

Typical tolerance to LoF variation

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.

1.15Z-score

OE missense 0.84 (0.77–0.92)

346 obs / 411.4 exp

Tolerant

Mild missense constraint

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.0.54 (0.38–0.80)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.77–0.92)

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.1.02

0≤1.21.6

LoF obs/exp: 19 / 34.9Missense obs/exp: 346 / 411.4Syn Z: -0.22

0.6937th %ile

GOF

0.7126th %ile

LOF

0.3550th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.