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]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismAD/ARLOEUF 0.253 OMIM phenotypes
Clinical SummaryADCY5
🧬
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.
📋
ClinVar Variants
57 unique Pathogenic / Likely Pathogenic· 408 VUS of 962 total submissions
📖
GeneReview available — ADCY5
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

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 (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.

LOF54% of P/LP variants are LoF · LOEUF 0.25
GOFprediction above median · 1 literature citation

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

962 submitted variants in ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic31
VUS408
Likely Benign321
Benign113
Conflicting55
26
Pathogenic
31
Likely Pathogenic
408
VUS
321
Likely Benign
113
Benign
55
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
8
1
0
26
Likely Pathogenic
14
17
0
0
31
VUS
5
375
23
5
408
Likely Benign
0
29
121
171
321
Benign
0
6
91
16
113
Conflicting
55
Total36435236192954

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap ADCY5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

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.

Search ClinicalTrials.gov →