ADCY5

Chr 3ADAR

adenylate cyclase 5

Also known as: AC5, DSKOD, FDFM

NCBI Gene: 111 ENSG00000173175 UniProt: O95622 OMIM: 600293

The protein encodes adenylyl cyclase 5, a membrane-bound enzyme that synthesizes cAMP in response to G protein-coupled receptor signaling and is inhibited by protein kinase A, calcium, and Gi alpha subunits. Mutations cause dyskinesia with orofacial involvement and neurodevelopmental disorder with hyperkinetic movements and dyskinesia through both autosomal dominant and autosomal recessive inheritance patterns. The high pLI score (0.999) and low LOEUF score (0.254) indicate the gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as a likely disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.253 OMIM phenotypes

Clinical Summary— ADCY5

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Gene-Disease Validity (ClinGen)

dyskinesia with orofacial involvement · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.14 (0.08–0.25)

0≤0.351.4

Missense OE?0.65 (0.60–0.70)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

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

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