BCKDK

Chr 16AR

branched chain keto acid dehydrogenase kinase

Also known as: BCKDKD, BDK

NCBI Gene: 10295ENSG00000103507UniProt: O14874

The branched-chain alpha-ketoacid dehydrogenase complex (BCKD) is an important regulator of the valine, leucine, and isoleucine catabolic pathways. The protein encoded by this gene is found in the mitochondrion, where it phosphorylates and inactivates BCKD. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

Primary Disease Associations & Inheritance

Branched-chain keto acid dehydrogenase kinase deficiencyMIM #614923
AR
115
ClinVar variants
21
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— BCKDK
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Gene-Disease Validity (ClinGen)
branched-chain keto acid dehydrogenase kinase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
21 Pathogenic / Likely Pathogenic· 53 VUS of 115 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.87LOEUF
pLI 0.000
Z-score 2.00
OE 0.51 (0.31–0.87)
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.
1.64Z-score
OE missense 0.73 (0.65–0.82)
209 obs / 287.1 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.0.51 (0.31–0.87)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.65–0.82)
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 / 19.6Missense obs/exp: 209 / 287.1Syn Z: -0.18

ClinVar Variant Classifications

115 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic7
VUS53
Likely Benign30
Benign6
Conflicting5
14
Pathogenic
7
Likely Pathogenic
53
VUS
30
Likely Benign
6
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
11
0
14
Likely Pathogenic
1
0
6
0
7
VUS
0
39
12
2
53
Likely Benign
0
1
12
17
30
Benign
0
0
4
2
6
Conflicting
—5
Total3414521115

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

View in ClinVar →

Protein Context — Lollipop Plot

BCKDK · 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

Branched-chain keto acid dehydrogenase kinase deficiency

MIM #614923

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Lymphatic Endothelial Branched-Chain Amino Acid Catabolic Defects Undermine Cardiac Lymphatic Integrity and Drive HFpEF.
Guo X et al.·Circulation
2025
BCKDK regulates breast cancer cell adhesion and tumor metastasis by inhibiting TRIM21 ubiquitinate talin1.
Xu C et al.·Cell Death Dis
2023
BCAA catabolism targeted therapy for heart failure with preserved ejection fraction.
Wang M et al.·Theranostics
2025
Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.
Zhou M et al.·Diabetes
2019
Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.
Filipski KJ et al.·J Med Chem
2025
Restoration of branched chain amino acid catabolism improves kidney function in preclinical cardiovascular-kidney-metabolic syndrome models.
Bollinger E et al.·Kidney Int
2025Functional
BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism.
Yang Q et al.·Mol Ther
2024
Branched-Chain α Keto-Acid Dehydrogenase Kinase-Mediated AKT Phosphorylation Promotes RCC Tumorigenesis and Drug Resistance.
Tian Q et al.·Adv Sci (Weinh)
2025
The plasma levels of CST and BCKDK in patients with sepsis.
Zhang B et al.·Peptides
2016Cohort
Novel Loss of Function Variant in BCKDK Causes a Treatable Developmental and Epileptic Encephalopathy.
Boemer F et al.·Int J Mol Sci
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A metabolic basis for motor deficits in mice lacking BCKDK.
Zhu L et al.·J Nutr Biochem
2026
PRSS55 regulates BCAA metabolism and interacts with BCKDK and BCKDHA in mouse testes and sperm.
Ge H et al.·Cell Biosci
2025🔓 Open AccessFunctional
CRISPR-RfxCas13d screening uncovers Bckdk as a post-translational regulator of maternal-to-zygotic transition in teleosts.
Hernández-Huertas L et al.·EMBO J
2025🔓 Open Access
BCKDK accelerates the progression of diabetic kidney disease by regulating leucine-mediated metabolic remodelling in renal tubular cells.
Shi C et al.·Diabetologia
2025Functional
BCKDK gene mutations as a rare condition responsible for comorbid neurodevelopmental delay, autism, and epilepsy: a case series of four patients.
Karimzadeh P et al.·Ann Med Surg (Lond)
2025🔓 Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools