ADCY9

Chr 16

adenylate cyclase 9

Also known as: AC9, ACIX

NCBI Gene: 115 ENSG00000162104 UniProt: O60503 OMIM: 603302

Adenylate cyclase 9 is a membrane-bound enzyme that catalyzes the formation of cyclic AMP from ATP in response to G protein-coupled receptor activation, contributing to signaling cascades involving corticotropin-releasing factor, corticosteroids, and beta-adrenergic receptors. Mutations in this highly constrained gene (pLI 0.98, LOEUF 0.31) cause autosomal recessive intellectual disability with hypotonia and behavioral abnormalities. The gene shows extreme intolerance to loss-of-function variants, suggesting that even heterozygous loss may have clinical consequences.

OMIM ResearchSummary from RefSeq, UniProt

Adenylate cyclase is a membrane bound enzyme that catalyses the formation of cyclic AMP from ATP. It is regulated by a family of G protein-coupled receptors, protein kinases, and calcium. The type 9 adenylyl cyclase is a widely distributed adenylyl cyclase, and it is stimulated by beta-adrenergic receptor activation but is insensitive to forskolin, calcium, and somatostatin. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.31

Clinical Summary— ADCY9

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

164 VUS of 214 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.979

Z-score 5.28

OE 0.17 (0.10–0.31)

Highly constrained

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

Missense Constraint?

1.25Z-score

OE missense 0.88 (0.83–0.93)

730 obs / 831.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.10–0.31)

0≤0.351.4

Missense OE?0.88 (0.83–0.93)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 8 / 47.2Missense obs/exp: 730 / 831.1Syn Z: -2.93

This gene — mechanism propensity

0.5280th %ile

GOF

0.6638th %ile

LOF

0.58top 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.

LOFLOEUF 0.31

GOFprediction above median

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.

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

ClinVar Variant Classifications

214 submitted variants in ClinVar

ClinVar

Classification Summary

VUS164

Likely Benign20

Benign11

164

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	164	0	0	164
Likely Benign	10	3	7	20
Benign	1	0	10	11
Total	175	3	17	195

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

View in ClinVar →

44 pathogenic / likely-pathogenic (of 56) ClinVar copy-number / structural variants overlap ADCY9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →