ADCY10

Chr 1AD

adenylate cyclase 10

Also known as: HCA2, HEL-S-7a, SAC, SACI, Sacy, hsAC

NCBI Gene: 55811 ENSG00000143199 UniProt: Q96PN6 OMIM: 605205

The protein catalyzes the formation of cAMP and functions as a bicarbonate/CO₂ sensor, with roles in spermatogenesis and ciliary beat regulation. Mutations cause autosomal dominant susceptibility to absorptive hypercalciuria. The gene shows minimal constraint against loss-of-function variants (pLI near 0, LOEUF ~1), suggesting tolerance to protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to a distinct class of adenylyl cyclases that is soluble and insensitive to G protein or forskolin regulation. Activity of this protein is regulated by bicarbonate. Variation at this gene has been observed in patients with absorptive hypercalciuria. Alternatively spliced transcript variants encoding different isoforms have been observed. There is a pseudogene of this gene on chromosome 6. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.031 OMIM phenotype

Clinical Summary— ADCY10

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Population Constraint (gnomAD)

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

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ClinVar Variants

36 unique Pathogenic / Likely Pathogenic· 325 VUS of 698 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.03LOEUF

pLI 0.000

Z-score 1.29

OE 0.85 (0.70–1.03)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.46Z-score

OE missense 0.96 (0.90–1.01)

788 obs / 824.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.85 (0.70–1.03)

0≤0.351.4

Missense OE?0.96 (0.90–1.01)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 69 / 81.5Missense obs/exp: 788 / 824.8Syn Z: -0.38

This gene — mechanism propensity

0.6551th %ile

GOF

0.6444th %ile

LOF

0.3453th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

ClinVar Variant Classifications

698 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic14

VUS325

Likely Benign182

Benign121

Conflicting12

Pathogenic

Likely Pathogenic

325

VUS

182

Likely Benign

121

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	0	2	0	22
Likely Pathogenic	14	0	0	0	14
VUS	4	305	13	3	325
Likely Benign	0	30	66	86	182
Benign	0	6	105	10	121
Conflicting	—				12
Total	38	341	186	99	676

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap ADCY10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →