# NM_002730.4(PRKACA):c.600C>T (p.Cys200=)

https://sugi.bio/variant/prkaca-p-cys200

## Summary

**PRKACA p.Cys200= (c.600C>T)** is classified **Likely benign** in PRKACA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). Ultra-rare (popmax 0.0201%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs769653802 · 1 submitter · ultra-rare (popmax 0.0201%, amr)

## For patients & families {#patients}

This is a change in the PRKACA gene that is classified as likely benign — not considered disease-causing, 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.Cys200= |
| Coding change (HGVS c.) | c.600C>T |
| MANE Select transcript | [NM_002730](https://www.ncbi.nlm.nih.gov/nuccore/NM_002730) |
| dbSNP | [rs769653802](https://www.ncbi.nlm.nih.gov/snp/rs769653802/) |
| Variant type | single nucleotide variant |
| Location | chr19:14097621-14097621 (GRCh38) |
| ClinVar | [VCV2649413](https://www.ncbi.nlm.nih.gov/clinvar/variation/2649413/) |

**All HGVS expressions:** `NC_000019.10:g.14097621G>A`, `NC_000019.9:g.14208433G>A`, `NG_029699.1:g.25127C>T`, `NM_001304349.2:c.828C>T`, `NM_002730.4:c.600C>T`, `NM_207518.3:c.576C>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 -2.308 — fast-evolving / accelerated position
- CADD: **PHRED 0.653**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.32 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0201%** (amr) · FAF95 0.0116% · FAF99 0.009% · 12/59,828 in the highest group · 36/1,612,236 alleles overall — ultra-rare (popmax 0.0201%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0201% | 4,986 |
| European (non-Finnish) | 0.00195% | 51,259 |
| African / African-American | 0.00134% | 74,866 |

*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 **200** lies in the protein kinase domain; 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.Cys200= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## 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 2026-10-06); 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 2649413). 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.*