ADCY1

Chr 7AR

adenylate cyclase 1

ENSG00000164742 UniProt: Q08828 OMIM: 103072

This protein catalyzes the formation of cAMP in response to G-protein signaling and is regulated by calcium/calmodulin, playing roles in memory, learning, and circadian rhythm regulation in the central nervous system and retina. Mutations cause autosomal recessive deafness (DFNB44), though the association remains provisional. The gene is highly constrained against loss-of-function variants (pLI 0.997), suggesting intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismARLOEUF 0.271 OMIM phenotype

Clinical Summary— ADCY1

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARLimited

Limited evidence — not for standalone diagnostic reporting

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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

0.27LOEUF

pLI 0.997

Z-score 5.51

OE 0.14 (0.08–0.27)

Highly constrained

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

Missense Constraint

4.38Z-score

OE missense 0.52 (0.48–0.57)

347 obs / 664.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.14 (0.08–0.27)

0≤0.351.4

Missense OE0.52 (0.48–0.57)

0≤0.61.4

Synonymous OE0.99

0≤1.21.6

LoF obs/exp: 7 / 48.4Missense obs/exp: 347 / 664.8Syn Z: 0.19

0.5772th %ile

GOF

0.7028th %ile

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.

LOFLOEUF 0.27

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.