ADCY5

Chr 3ADAR

adenylate cyclase 5

Also known as: AC5, DSKOD, FDFM

This gene encodes a member of the membrane-bound adenylyl cyclase enzymes. Adenylyl cyclases mediate G protein-coupled receptor signaling through the synthesis of the second messenger cAMP. Activity of the encoded protein is stimulated by the Gs alpha subunit of G protein-coupled receptors and is inhibited by protein kinase A, calcium and Gi alpha subunits. Single nucleotide polymorphisms in this gene may be associated with low birth weight and type 2 diabetes. Alternatively spliced transcript variants that encode different isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

OMIMResearchGenerating clinical summary…
MultiplemechanismAD/ARLOEUF 0.253 OMIM phenotypes
Clinical SummaryADCY5
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Gene-Disease Validity (ClinGen)
dyskinesia with orofacial involvement · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint?
0.25LOEUF
pLI 0.999
Z-score 5.77
OE 0.14 (0.080.25)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?
3.40Z-score
OE missense 0.65 (0.600.70)
491 obs / 754.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?
LoF OE?0.14 (0.080.25)
00.351.4
Missense OE?0.65 (0.600.70)
00.61.4
Synonymous OE?0.99
01.21.6
LoF obs/exp: 7 / 51.8Missense obs/exp: 491 / 754.1Syn Z: 0.09
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongADCY5-related developmental disorderOTHERAD

This gene — mechanism propensity

DN
0.5379th %ile
GOF
0.73top 25%
LOF
0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation
LOFLOEUF 0.25

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.

Literature Evidence

GOFGain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.1

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

References

  1. 1.PMID 24700542

ClinVar Variant Classifications

0 submitted variants 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.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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