# NM_002730.4(PRKACA):c.790T>C (p.Ser264Pro)

https://sugi.bio/variant/prkaca-p-ser264pro

## Summary

**PRKACA p.Ser264Pro (c.790T>C)** is classified **Uncertain significance** in PRKACA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-26). AlphaMissense: likely benign (0.1415); Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs775116225 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the PRKACA 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 | [PRKACA](https://sugi.bio/atlas/gene/PRKACA/) |
| Protein change (HGVS p.) | p.Ser264Pro |
| Coding change (HGVS c.) | c.790T>C |
| MANE Select transcript | [NM_002730](https://www.ncbi.nlm.nih.gov/nuccore/NM_002730) |
| dbSNP | [rs775116225](https://www.ncbi.nlm.nih.gov/snp/rs775116225/) |
| Variant type | single nucleotide variant |
| Location | chr19:14093768-14093768 (GRCh38) |
| ClinVar | [VCV2541259](https://www.ncbi.nlm.nih.gov/clinvar/variation/2541259/) |

**All HGVS expressions:** `NC_000019.10:g.14093768A>G`, `NC_000019.9:g.14204580A>G`, `NG_029699.1:g.28980T>C`, `NM_001304349.2:c.1018T>C`, `NM_002730.4:c.790T>C`, `NM_207518.3:c.766T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1415)
- REVEL 0.375 (indeterminate)
- SaProt LLR -10.143 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 9.28, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.0**. 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 0.39** across the covering region of the MANE Select transcript (14,093,674–14,100,889), spanning 7,215 bp. Chi-square p 3e-21. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.000124% · FAF99 9e-05% · 1/59,910 in the highest group · 6/1,613,638 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,910 |
| European (non-Finnish) | 0.000424% | 235,956 |

*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}

**PRKACA** population constraint: LOEUF 0.338, pLI 0.99999, missense-Z 3.8454. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **264** lies in the protein kinase domain; a UniProt-annotated variant site (in); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 95.92, 95% of residues very-high.

**54 experimental structure(s)** (PDB): [2GU8](https://www.rcsb.org/structure/2GU8), [3AGL](https://www.rcsb.org/structure/3AGL), [3AGM](https://www.rcsb.org/structure/3AGM), [3AMA](https://www.rcsb.org/structure/3AMA), [3AMB](https://www.rcsb.org/structure/3AMB), [3L9L](https://www.rcsb.org/structure/3L9L) — incl. mutant structure 3AMA.

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

*Describes the biological roles of PRKACA (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:** PRKACA's established molecular role includes protein serine/threonine kinase activity. p.Ser264Pro falls in the protein kinase domain. In Reactome, PRKACA is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**, **FCGR3A-mediated IL10 synthesis**.

**Disease mechanism (Reactome):** PRKACA loss or alteration is curated in [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821), [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323), [Loss of phosphorylation of MECP2 at T308](https://reactome.org/content/detail/R-HSA-9022535).

### Pathways affected {#pathways}

PRKACA participates in **39 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821) | electronic |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | electronic |
| ⚕ [Loss of phosphorylation of MECP2 at T308](https://reactome.org/content/detail/R-HSA-9022535) | electronic |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | 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 |
| [GLI3 is processed to GLI3R by the proteasome](https://reactome.org/content/detail/R-HSA-5610785) | curated |
| [HDL assembly](https://reactome.org/content/detail/R-HSA-8963896) | 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 |
| [Interleukin-3, Interleukin-5 and GM-CSF signaling](https://reactome.org/content/detail/R-HSA-512988) | curated |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | 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 |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | curated |
| [Rap1 signalling](https://reactome.org/content/detail/R-HSA-392517) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |
| [Vasopressin regulates renal water homeostasis via Aquaporins](https://reactome.org/content/detail/R-HSA-432040) | curated |
| [CREB1 phosphorylation through the activation of Adenylate Cyclase](https://reactome.org/content/detail/R-HSA-442720) | electronic |
| [Degradation of GLI1 by the proteasome](https://reactome.org/content/detail/R-HSA-5610780) | electronic |
| [Degradation of GLI2 by the proteasome](https://reactome.org/content/detail/R-HSA-5610783) | electronic |
| [GPER1 signaling](https://reactome.org/content/detail/R-HSA-9634597) | electronic |
| [Glucagon-like Peptide-1 (GLP1) regulates insulin secretion](https://reactome.org/content/detail/R-HSA-381676) | electronic |
| [PKA-mediated phosphorylation of CREB](https://reactome.org/content/detail/R-HSA-111931) | electronic |
| [PKA-mediated phosphorylation of key metabolic factors](https://reactome.org/content/detail/R-HSA-163358) | electronic |
| [ROBO receptors bind AKAP5](https://reactome.org/content/detail/R-HSA-9010642) | electronic |
| [Regulation of MECP2 expression and activity](https://reactome.org/content/detail/R-HSA-9022692) | electronic |
| [Regulation of glycolysis by fructose 2,6-bisphosphate metabolism](https://reactome.org/content/detail/R-HSA-9634600) | electronic |
| [Triglyceride catabolism](https://reactome.org/content/detail/R-HSA-163560) | electronic |

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

**Molecular function:** protein serine/threonine kinase activity, cAMP-dependent protein kinase activity, protein serine/threonine/tyrosine kinase activity, potassium channel inhibitor activity, protein kinase binding, protein kinase A regulatory subunit binding.

**Biological process:** mRNA processing, adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway, intracellular potassium ion homeostasis, cellular response to heat, positive regulation of cholesterol biosynthetic process, regulation of osteoblast differentiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-26.

**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 | 2023-04-26 |

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

## Similar variants {#similar}

Related PRKACA variant pages (same residue, condition, or type): [PRKACA p.Gly137Arg](/variant/prkaca-p-gly137arg), [PRKACA p.Arg271Trp](/variant/prkaca-p-arg271trp), [PRKACA p.Asn341Ser](/variant/prkaca-p-asn341ser), [PRKACA p.Gly67Arg](/variant/prkaca-p-gly67arg), [PRKACA c.109-6C>T](/variant/prkaca-c-109-minus-6c-t), [PRKACA c.47-418C>T](/variant/prkaca-c-47-minus-418c-t), [PRKACA p.Arg281=](/variant/prkaca-p-arg281), [PRKACA p.Gly127=](/variant/prkaca-p-gly127).

### 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 2541259). 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.*