# NM_020546.3(ADCY2):c.2386C>G (p.Pro796Ala)

https://sugi.bio/variant/adcy2-p-pro796ala

## Summary

**ADCY2 p.Pro796Ala (c.2386C>G)** is classified **Uncertain significance** in ADCY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely benign (0.1778); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ADCY2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADCY2](https://sugi.bio/atlas/gene/ADCY2/) |
| Protein change (HGVS p.) | p.Pro796Ala |
| Coding change (HGVS c.) | c.2386C>G |
| MANE Select transcript | [NM_020546](https://www.ncbi.nlm.nih.gov/nuccore/NM_020546) |
| Variant type | single nucleotide variant |
| Location | chr5:7784366-7784366 (GRCh38) |
| ClinVar | [VCV3494528](https://www.ncbi.nlm.nih.gov/clinvar/variation/3494528/) |

**All HGVS expressions:** `NC_000005.10:g.7784366C>G`, `NC_000005.9:g.7784479C>G`, `NG_046913.1:g.393137C>G`, `NM_020546.3:c.2386C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1778)
- REVEL 0.489 (indeterminate)
- SaProt LLR -6.611 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.945, GERP 2.33, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.3**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.47** across the covering region of the MANE Select transcript (7,773,096–7,826,868), spanning 53,772 bp. Chi-square p 9.7e-25. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.07**, donor loss **0.00**, acceptor gain **0.31**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.31**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ADCY2** population constraint: LOEUF 0.329, pLI 1, missense-Z 4.9485. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.91, 35% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ADCY2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ADCY2 participates in disease-associated pathways. In Reactome, ADCY2 is annotated in disease pathway(s) including **FCGR3A-mediated IL10 synthesis**, **ADORA2B mediated anti-inflammatory cytokines production**.

**Disease mechanism (Reactome):** ADCY2 loss or alteration is curated in [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323), [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821).

### Pathways affected {#pathways}

ADCY2 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | curated |
| ⚕ [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821) | electronic |
| [Adenylate cyclase activating pathway](https://reactome.org/content/detail/R-HSA-170660) | curated |
| [Glucagon signaling in metabolic regulation](https://reactome.org/content/detail/R-HSA-163359) | curated |
| [Hedgehog 'off' state](https://reactome.org/content/detail/R-HSA-5610787) | curated |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | curated |
| [PKA activation](https://reactome.org/content/detail/R-HSA-163615) | curated |
| [PKA activation in glucagon signalling](https://reactome.org/content/detail/R-HSA-164378) | curated |
| [Vasopressin regulates renal water homeostasis via Aquaporins](https://reactome.org/content/detail/R-HSA-432040) | curated |
| [Adenylate cyclase inhibitory pathway](https://reactome.org/content/detail/R-HSA-170670) | electronic |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | electronic |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | electronic |
| [G alpha (z) signalling events](https://reactome.org/content/detail/R-HSA-418597) | electronic |
| [GPER1 signaling](https://reactome.org/content/detail/R-HSA-9634597) | electronic |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-15 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ADCY2 variant pages (same residue, condition, or type): [ADCY2 p.Arg842Gln](/variant/adcy2-p-arg842gln), [ADCY2 c.2094+16C>T](/variant/adcy2-c-2094-plus-16c-t), [ADCY2 c.2094+6T>C](/variant/adcy2-c-2094-plus-6t-c), [ADCY2 p.Cys887=](/variant/adcy2-p-cys887), [ADCY2 p.Ser928=](/variant/adcy2-p-ser928), [ADCY2 p.Ala634Val](/variant/adcy2-p-ala634val), [ADCY2 p.Ala63Gly](/variant/adcy2-p-ala63gly), [ADCY2 p.Ala694Asp](/variant/adcy2-p-ala694asp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3494528). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*