# NM_002734.5(PRKAR1A):c.267A>T (p.Pro89=)

https://sugi.bio/variant/prkar1a-p-pro89

## Summary

**PRKAR1A p.Pro89= (c.267A>T)** is classified **Likely benign** in PRKAR1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-06). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs2509399076 · 2 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PRKAR1A gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRKAR1A](https://sugi.bio/atlas/gene/PRKAR1A/) |
| Protein change (HGVS p.) | p.Pro89= |
| Coding change (HGVS c.) | c.267A>T |
| MANE Select transcript | [NM_002734](https://www.ncbi.nlm.nih.gov/nuccore/NM_002734) |
| dbSNP | [rs2509399076](https://www.ncbi.nlm.nih.gov/snp/rs2509399076/) |
| Variant type | single nucleotide variant |
| Location | chr17:68522845-68522845 (GRCh38) |
| ClinVar | [VCV1794649](https://www.ncbi.nlm.nih.gov/clinvar/variation/1794649/) |

**All HGVS expressions:** `LRG_514:g.114223A>T`, `LRG_514t1:c.267A>T`, `LRG_514t2:c.267A>T`, `NC_000017.10:g.66518986A>T`, `NC_000017.11:g.68522845A>T`, `NG_007093.3:g.114223A>T`, `NM_001276289.2:c.267A>T`, `NM_001276290.1:c.267A>T`, `NM_001278433.2:c.267A>T`, `NM_001369389.1:c.267A>T`, `NM_001369390.1:c.267A>T`, `NM_002734.5:c.267A>T`, `NM_212471.3:c.267A>T`, `NM_212472.2:c.267A>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -4.905, GERP -4.35 — fast-evolving / accelerated position
- CADD: **PHRED 0.868**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**PRKAR1A** population constraint: LOEUF 0.158, pLI 1, missense-Z 4.1536; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Carney complex, type 1** — Definitive (AD)

## Protein context {#protein}

Residue **89** lies in the 'dimerization and phosphorylation' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 87.95, 62% of residues very-high.

**3 experimental structure(s)** (PDB): [5KJX](https://www.rcsb.org/structure/5KJX), [5KJY](https://www.rcsb.org/structure/5KJY), [5KJZ](https://www.rcsb.org/structure/5KJZ) — incl. mutant structure 5KJY.

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

*Describes the biological roles of PRKAR1A (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:** PRKAR1A's established molecular role includes cAMP-dependent protein kinase inhibitor activity. p.Pro89= falls in the dimerization and phosphorylation region. In Reactome, PRKAR1A is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**, **ALK mutants bind TKIs**.

**Disease mechanism (Reactome):** PRKAR1A loss or alteration is curated in [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821), [ALK mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9700645), [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323).

### Pathways affected {#pathways}

PRKAR1A participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821) | curated |
| ⚕ [ALK mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9700645) | curated |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [CREB1 phosphorylation through the activation of Adenylate Cyclase](https://reactome.org/content/detail/R-HSA-442720) | curated |
| [DARPP-32 events](https://reactome.org/content/detail/R-HSA-180024) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [GPER1 signaling](https://reactome.org/content/detail/R-HSA-9634597) | 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 |
| [Glucagon-like Peptide-1 (GLP1) regulates insulin secretion](https://reactome.org/content/detail/R-HSA-381676) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cAMP-dependent protein kinase inhibitor activity, cAMP-dependent protein kinase regulator activity, protein domain specific binding, cAMP binding, ubiquitin protein ligase binding, protein kinase A catalytic subunit binding.

**Biological process:** negative regulation of gene expression, negative regulation of activated T cell proliferation, negative regulation of cAMP/PKA signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-06.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-03-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-06 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Carney complex, type 1](https://sugi.bio/atlas/disease/carney-complex-type-1/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Carney complex, type 1, Tumor predisposition, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, CARNEY COMPLEX, TYPE I, CARNEY MYXOMA-ENDOCRINE COMPLEX.

## Similar variants {#similar}

Related PRKAR1A variant pages (same residue, condition, or type): [PRKAR1A c.502+1G>A](/variant/prkar1a-c-502-plus-1g-a), [PRKAR1A c.549+1G>A](/variant/prkar1a-c-549-plus-1g-a), [PRKAR1A c.891+1G>A](/variant/prkar1a-c-891-plus-1g-a), [PRKAR1A c.891+3A>G](/variant/prkar1a-c-891-plus-3a-g), [PRKAR1A c.892-2A>G](/variant/prkar1a-c-892-minus-2a-g), [PRKAR1A p.Arg16Ter](/variant/prkar1a-p-arg16ter), [PRKAR1A p.Arg228Ter](/variant/prkar1a-p-arg228ter), [PRKAR1A p.Arg335Cys](/variant/prkar1a-p-arg335cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1794649). 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.*