PDE10A

Chr 6ARAD

phosphodiesterase 10A

Also known as: ADSD2, HSPDE10A, IOLOD, PDE10A19

NCBI Gene: 10846ENSG00000112541UniProt: Q9Y233

The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase family. It plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This protein can hydrolyze both cAMP and cGMP to the corresponding nucleoside 5' monophosphate, but has higher affinity for cAMP, and is more efficient with cAMP as substrate. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2011]

Primary Disease Associations & Inheritance

Dyskinesia, limb and orofacial, infantile-onsetMIM #616921
AR
Striatal degeneration, autosomal dominantMIM #616922
AD
341
ClinVar variants
57
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— PDE10A
⚡
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
57 Pathogenic / Likely Pathogenic· 143 VUS of 341 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.21LOEUF
pLI 1.000
Z-score 5.51
OE 0.09 (0.04–0.21)
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.
3.76Z-score
OE missense 0.50 (0.45–0.56)
222 obs / 445.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.09 (0.04–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.50 (0.45–0.56)
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.0.97
0≤1.21.6
LoF obs/exp: 4 / 43.0Missense obs/exp: 222 / 445.1Syn Z: 0.26

ClinVar Variant Classifications

341 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48
Likely Pathogenic9
VUS143
Likely Benign116
Benign21
Conflicting4
48
Pathogenic
9
Likely Pathogenic
143
VUS
116
Likely Benign
21
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
45
0
48
Likely Pathogenic
2
5
2
0
9
VUS
8
106
25
4
143
Likely Benign
0
4
52
60
116
Benign
0
0
11
10
21
Conflicting
—4
Total1011813574341

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

View in ClinVar →

Protein Context — Lollipop Plot

PDE10A · protein map & ClinVar variants

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

Gene2Phenotype Curations

PDE10A-related childhood-onset chorea with bilateral striatal lesions

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Dyskinesia, limb and orofacial, infantile-onset

MIM #616921

Molecular basis of disorder known

Autosomal recessive

Striatal degeneration, autosomal dominant

MIM #616922

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth.
Chen S et al.·Circ Res
2023
The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders.
Pérez-Dueñas B et al.·Mov Disord
2022
Chorea.
Termsarasab P·Continuum (Minneap Minn)
2019Review
Autoimmune brainstem encephalitis: Clinical associations, outcomes, and proposed diagnostic criteria.
Gilligan M et al.·Ann Clin Transl Neurol
2025
New Drug Treatments for Schizophrenia: A Review of Approaches to Target Circuit Dysfunction.
Howes OD et al.·Biol Psychiatry
2024Review
Current Understanding of PDE10A in the Modulation of Basal Ganglia Circuitry.
Schülke JP et al.·Adv Neurobiol
2017Review
Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice.
Cheng J et al.·Autophagy
2020
Advances in the Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 2: Focus on Schizophrenia.
Świerczek A et al.·Curr Drug Targets
2019Review
Patented PDE10A inhibitors: novel compounds since 2007.
Kehler J et al.·Expert Opin Ther Pat
2009Review
PDE10A Mutation as an Emerging Cause of Childhood-Onset Hyperkinetic Movement Disorders: A Review of All Published Cases.
Kalampokini S et al.·Neuropediatrics
2024Review
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
Huntington Disease

IMarkHD: in Vivo Longitudinal Imaging of HD Pathology

RECRUITING
NCT03434548King's College LondonStarted 2021-07-20
PET imagingMulti-modal MRI imaging

External Resources

Links to major genomics databases and tools