CDKN1B

Chr 12AD

cyclin dependent kinase inhibitor 1B

Also known as: CDKN4, KIP1, MEN1B, MEN4, P27KIP1

NCBI Gene: 1027 ENSG00000111276 UniProt: P46527

This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]

Primary Disease Associations & Inheritance

Multiple endocrine neoplasia, type IVMIM #610755

Active trials

Pathogenic / LP

496

ClinVar variants

Pubs (1 yr)

-1.8

Missense Z

0.65

LOEUF

Clinical Summary— CDKN1B

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Gene-Disease Validity (ClinGen)

multiple endocrine neoplasia type 4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.62) — some intolerance to loss-of-function variants.

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ClinVar Variants

84 Pathogenic / Likely Pathogenic· 279 VUS of 496 total submissions

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GeneReview available — CDKN1B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.65LOEUF

pLI 0.624

Z-score 2.17

OE 0.14 (0.05–0.65)

Moderately constrained

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.

-1.85Z-score

OE missense 1.50 (1.32–1.70)

164 obs / 109.6 exp

Tolerant

Tolerant to missense variation

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.0.14 (0.05–0.65)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.50 (1.32–1.70)

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.1.99

0≤1.21.6

LoF obs/exp: 1 / 7.4Missense obs/exp: 164 / 109.6Syn Z: -5.17

0.3793th %ile

GOF

0.3491th %ile

LOF

0.66top 25%

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

LOFprediction above median · 1 literature citation · 57% of P/LP variants are LoF

Literature Evidence

LOFClinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and Review of Published CasesPMID:30990521

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