DSTYK

Chr 1ADAR

dual serine/threonine and tyrosine protein kinase

Also known as: CAKUT1, DustyPK, HDCMD38P, RHDNS1, RIP5, RIPK5, SPG23

NCBI Gene: 25778ENSG00000133059UniProt: Q6XUX3

This gene encodes a dual serine/threonine and tyrosine protein kinase which is expressed in multiple tissues. It is thought to function as a regulator of cell death. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

Primary Disease Associations & Inheritance

Congenital anomalies of kidney and urinary tract 1MIM #610805
AD
Spastic paraplegia 23, autosomal recessiveMIM #270750
AR
372
ClinVar variants
20
Pathogenic / LP
0.51
pLI score
0
Active trials
Clinical Summary— DSTYK
🧬
Gene-Disease Validity (ClinGen)
complex hereditary spastic paraplegia · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.51) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 228 VUS of 372 total submissions

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.
0.37LOEUF
pLI 0.513
Z-score 4.90
OE 0.22 (0.13–0.37)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.59Z-score
OE missense 0.81 (0.75–0.87)
434 obs / 537.5 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.0.22 (0.13–0.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.75–0.87)
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: 10 / 45.8Missense obs/exp: 434 / 537.5Syn Z: -0.17

ClinVar Variant Classifications

372 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic5
VUS228
Likely Benign87
Benign27
Conflicting10
15
Pathogenic
5
Likely Pathogenic
228
VUS
87
Likely Benign
27
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
14
0
15
Likely Pathogenic
2
1
2
0
5
VUS
5
208
13
2
228
Likely Benign
0
7
22
58
87
Benign
0
3
19
5
27
Conflicting
—10
Total82197065372

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

View in ClinVar →

Protein Context — Lollipop Plot

DSTYK · protein map & ClinVar variants

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

Gene2Phenotype Curations

DSTYK-related complicated spastic paraparesis

strong
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

DSTYK-related congenital anomalies of kidney and urinary tract, CAKUT

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Congenital anomalies of kidney and urinary tract 1

MIM #610805

Molecular basis of disorder known

Autosomal dominant

Spastic paraplegia 23, autosomal recessive

MIM #270750

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
DSTYK Inhibition Sensitizes NSCLC to Taxane-Based Chemotherapy.
Echepare M et al.·J Thorac Oncol
2025
Eating away T cell responses in lung cancer.
Ferrara R et al.·J Exp Med
2022
DSTYK phosphorylates STING at late endosomes to promote STING signaling.
Dong H et al.·EMBO Rep
2025
Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies.
Martino J et al.·Genet Med
2023Functional
DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity.
Valencia K et al.·J Exp Med
2022
Mutations in DSTYK and dominant urinary tract malformations.
Sanna-Cherchi S et al.·N Engl J Med
2013
Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia.
Yun Z et al.·Comput Biol Med
2024Cohort
A DSTYK mutation activates ERK1/2 signaling to promote intraspinal dissemination in a case of solitary fibrous tumor/hemangiopericytoma.
Tang G et al.·Lab Invest
2019Case report
Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis.
Wu H et al.·Am J Nephrol
2017Cohort
Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis.
Boissel S et al.·Genet Med
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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