PDE10A

Chr 6ARAD

phosphodiesterase 10A

Also known as: ADSD2, HSPDE10A, IOLOD, PDE10A19

NCBI Gene: 10846 ENSG00000112541 UniProt: Q9Y233 OMIM: 610652

This enzyme hydrolyzes cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to regulate intracellular signaling, with higher affinity and efficiency for cAMP. Mutations cause infantile-onset limb and orofacial dyskinesia or autosomal dominant striatal degeneration, following either autosomal recessive or autosomal dominant inheritance patterns. The protein is essential for normal neurological function, as evidenced by its very high intolerance to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.212 OMIM phenotypes

Clinical Summary— PDE10A

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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.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 136 VUS of 310 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.09 (0.04–0.21)

0≤0.351.4

Missense OE?0.50 (0.45–0.56)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 4 / 43.0Missense obs/exp: 222 / 445.1Syn Z: 0.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPDE10A-related childhood-onset chorea with bilateral striatal lesionsOTHERAD

This gene — mechanism propensity

0.5378th %ile

GOF

0.6541th %ile

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF38% of P/LP variants are LoF · LOEUF 0.21

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

310 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic9

VUS136

Likely Benign117

Benign21

Conflicting4

Pathogenic

Likely Pathogenic

136

VUS

117

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	3	0	0	4
Likely Pathogenic	4	5	0	0	9
VUS	12	111	9	4	136
Likely Benign	0	4	52	61	117
Benign	0	0	11	10	21
Conflicting	—				4
Total	17	123	72	75	291

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

View in ClinVar →

48 pathogenic / likely-pathogenic (of 60) ClinVar copy-number / structural variants overlap PDE10A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →