HIPK2

Chr 7

homeodomain interacting protein kinase 2

Also known as: PRO0593

NCBI Gene: 28996ENSG00000064393UniProt: Q9H2X6

This gene encodes a conserved serine/threonine kinase that is a member of the homeodomain-interacting protein kinase family. The encoded protein interacts with homeodomain transcription factors and many other transcription factors such as p53, and can function as both a corepressor and a coactivator depending on the transcription factor and its subcellular localization. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

62
ClinVar variants
18
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— HIPK2
⚡
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
18 Pathogenic / Likely Pathogenic· 37 VUS of 62 total submissions

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.
0.16LOEUF
pLI 1.000
Z-score 6.14
OE 0.06 (0.03–0.16)
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.
2.86Z-score
OE missense 0.70 (0.65–0.75)
509 obs / 726.0 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.0.06 (0.03–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.65–0.75)
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.0.94
0≤1.21.6
LoF obs/exp: 3 / 49.7Missense obs/exp: 509 / 726.0Syn Z: 0.82

ClinVar Variant Classifications

62 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic1
VUS37
Likely Benign7
17
Pathogenic
1
Likely Pathogenic
37
VUS
7
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
17
0
17
Likely Pathogenic
0
0
1
0
1
VUS
0
35
2
0
37
Likely Benign
0
0
0
7
7
Benign
0
0
0
0
0
Total03520762

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

View in ClinVar →

Protein Context — Lollipop Plot

HIPK2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Modulation of TGF-β signaling new approaches toward kidney disease and fibrosis therapy.
Hong Q et al.·Int J Biol Sci
2025Review
Inactivation of HIPK2 attenuates KRAS(G12D) activity and prevents pancreatic tumorigenesis.
Sozzi S et al.·J Exp Clin Cancer Res
2024
KLF15 regulates macrophage polarization patterns in deep vein thrombosis.
Li J et al.·Int Immunopharmacol
2025
HIPK2 Cooperates with KRAS Signaling and Associates with Colorectal Cancer Progression.
Di Segni M et al.·Mol Cancer Res
2022
Identification of Senomorphic miRNAs in Embryonic Progenitor and Adult Stem Cell-Derived Extracellular Vesicles.
Zhang T et al.·Aging Cell
2025
An Alternative Splice Variant of HIPK2 with Intron Retention Contributes to Cytokinesis.
Gatti V et al.·Cells
2020
HIPK2 C-terminal domain inhibits NF-κB signaling and renal inflammation in kidney injury.
Feng Y et al.·JCI Insight
2024
HIPK2 role in the tumor-host interaction: Impact on fibroblasts transdifferentiation CAF-like.
Garufi A et al.·IUBMB Life
2019
CircHIPK2 facilitates phenotypic switching of vascular smooth muscle cells in hypertension.
Liu C et al.·J Hum Hypertens
2023
HIPK2 Overexpression and Its Prognostic Role in Human Papillomavirus-Positive Tonsillar Squamous Cell Carcinoma.
Kwon MJ et al.·Biomed Res Int
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
HDAC6 regulates the protein stability and tumor suppressor function of HIPK2 independently of its deacetylase activity.
Joo BR et al.·Biochem Biophys Res Commun
2026
CircRNA HIPK2-mediated metabolic reprogramming restores mitochondrial homeostasis in chondrocytes through the miR-206/Sirt3 signaling axis attenuating osteoarthritis-induced nociception.
Shen J et al.·Inflammopharmacology
2026
Fragment-based discovery, dynamics simulation and pharmacological study of 2-amino-pyrimidine derivative as HIPK2 inhibitor.
Wu Y et al.·Chem Biol Interact
2025
HIPK2 Confers Protection Against Septic Myocardial Injury by Regulating Ferroptosis.
Cui K et al.·Cardiovasc Toxicol
2025
Exploring the role of diosgenin in modulating RUNX1 and HIPK2 transcription to mitigate Primary Sjögren's Syndrome.
Pan Y et al.·Immunobiology
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools