ADCY5

Chr 3ADAR

adenylate cyclase 5

NCBI Gene: 111ENSG00000173175UniProt: O95622

Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:15385642, PubMed:24700542, PubMed:26206488). Mediates signaling downstream of ADRB1 (PubMed:24700542). Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (PubMed:24740569)

Primary Disease Associations & Inheritance

Dyskinesia with orofacial involvement, autosomal dominantMIM #606703
AD
Dyskinesia with orofacial involvement, autosomal recessiveMIM #619647
AR
Neurodevelopmental disorder with hyperkinetic movements and dyskinesiaMIM #619651
AR
973
ClinVar variants
22
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ADCY5
⚡
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
22 Pathogenic / Likely Pathogenic· 236 VUS of 973 total submissions

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.
0.25LOEUF
pLI 0.999
Z-score 5.77
OE 0.14 (0.08–0.25)
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.
3.40Z-score
OE missense 0.65 (0.60–0.70)
491 obs / 754.1 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.0.14 (0.08–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.65 (0.60–0.70)
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.0.99
0≤1.21.6
LoF obs/exp: 7 / 51.8Missense obs/exp: 491 / 754.1Syn Z: 0.09

ClinVar Variant Classifications

973 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic9
VUS236
Likely Benign150
Benign65
Conflicting19
13
Pathogenic
9
Likely Pathogenic
236
VUS
150
Likely Benign
65
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
3
4
0
13
Likely Pathogenic
3
3
3
0
9
VUS
2
215
17
2
236
Likely Benign
0
8
61
81
150
Benign
0
3
61
1
65
Conflicting
—19
Total1123214684492

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

View in ClinVar →

Protein Context — Lollipop Plot

ADCY5 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ADCY5-related developmental disorder

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 with orofacial involvement, autosomal dominant

MIM #606703

Molecular basis of disorder known

Autosomal dominant

Dyskinesia with orofacial involvement, autosomal recessive

MIM #619647

Molecular basis of disorder known

Autosomal recessive

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia

MIM #619651

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
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
An Update on the Phenotype, Genotype and Neurobiology of ADCY5-Related Disease.
Ferrini A et al.·Mov Disord
2021Review
ADCY5-related dyskinesia - case series with literature review.
Kozon K et al.·Neurol Neurochir Pol
2024Review
[ADCY5-associated dyskinesia in young children: a case report of a family and an updated review].
Aguilera-Nieto L et al.·Rev Neurol
2020Review
ADCY5-Mosaic Variants: A Diagnosis Not to Be Missed.
Innocenti A et al.·Mov Disord Clin Pract
2025Case report
Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large-Scale Exome Sequencing.
Thomsen M et al.·Ann Clin Transl Neurol
2025
Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study.
Méneret A et al.·Mov Disord
2022
Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders.
Bohlega SA et al.·Parkinsonism Relat Disord
2019
Atypical ADCY5-related movement disorders: Highlighting adolescent/adult-onset cervical dystonia.
Quazza F et al.·Parkinsonism Relat Disord
2025Case report
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