ADCY8

Chr 8

adenylate cyclase 8

Also known as: AC8, ADCY3, HBAC1

NCBI Gene: 114 ENSG00000155897 UniProt: P40145 OMIM: 103070

Adenylyl cyclase 8 is a membrane-bound enzyme that catalyzes the formation of cyclic AMP from ATP in response to calcium entry, playing critical roles in synaptic plasticity, learning and memory, and insulin secretion. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in early infancy with seizures and severe developmental delays. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

Adenylate cyclase is a membrane bound enzyme that catalyses the formation of cyclic AMP from ATP. The enzymatic activity is under the control of several hormones, and different polypeptides participate in the transduction of the signal from the receptor to the catalytic moiety. Stimulatory or inhibitory receptors (Rs and Ri) interact with G proteins (Gs and Gi) that exhibit GTPase activity and they modulate the activity of the catalytic subunit of the adenylyl cyclase [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.54

Clinical Summary— ADCY8

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

150 VUS of 169 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.000

Z-score 4.32

OE 0.37 (0.26–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.57Z-score

OE missense 0.83 (0.78–0.89)

599 obs / 717.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.26–0.54)

0≤0.351.4

Missense OE?0.83 (0.78–0.89)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 20 / 54.3Missense obs/exp: 599 / 717.4Syn Z: 0.25

This gene — mechanism propensity

0.76top 25%

GOF

0.79top 25%

LOF

0.3261th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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

DNprediction 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.

ClinVar Variant Classifications

169 submitted variants in ClinVar

ClinVar

Classification Summary

VUS150

Likely Benign2

Benign4

150

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	150	0	150
Likely Benign	0	2	2
Benign	0	4	4
Total	150	6	156

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap ADCY8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →