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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Dyskinesia with orofacial involvement, autosomal dominantMIM #606703

Dyskinesia with orofacial involvement, autosomal recessiveMIM #619647

Neurodevelopmental disorder with hyperkinetic movements and dyskinesiaMIM #619651

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · dyskinesia with orofacial involvement · SD · ClinGen 2024
Strong · dyskinesia with orofacial involvement, autosomal dominant · AD · Labcorp Genetics (formerly Invitae)
Strong · neurodevelopmental disorder with hyperkinetic movements and dyskinesia · AR · Labcorp Genetics (formerly Invitae)
Strong · neurodevelopmental disorder · AD · G2P

+2 more curated pairs

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.25

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — ADCY5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in ADCY5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 37

1,498 rare PASS variants

Rare truncating (LoF)

1 in 1,900

130 rare PASS variants

Rare synonymous (reference)

1 in 43

836 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ADCY5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 47	1 in 2,300
South Asian	~43k	1 in 37	1 in 580
Remaining (unassigned)	~30k	1 in 32	1 in 2,100
European (Finnish)	~27k	1 in 110	1 in 1,200
Admixed American	~22k	1 in 40	1 in 890
African / African American	~21k	1 in 37	1 in 2,000
East Asian	~20k	1 in 56	1 in 2,700
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 2,700
Middle Eastern	~2,884	1 in 50	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.