# NM_003488.4(AKAP1):c.2454G>A (p.Pro818=)

https://sugi.bio/variant/akap1-p-pro818

## Summary

**AKAP1 p.Pro818= (c.2454G>A)** is classified **Benign** in AKAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-19). Low-frequency (popmax 3.39%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs116339701 · 2 submitters · low-frequency (popmax 3.39%, afr)

## For patients & families {#patients}

This is a change in the AKAP1 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [AKAP1](https://sugi.bio/atlas/gene/AKAP1/) |
| Protein change (HGVS p.) | p.Pro818= |
| Coding change (HGVS c.) | c.2454G>A |
| MANE Select transcript | [NM_003488](https://www.ncbi.nlm.nih.gov/nuccore/NM_003488) |
| dbSNP | [rs116339701](https://www.ncbi.nlm.nih.gov/snp/rs116339701/) |
| Variant type | single nucleotide variant |
| Location | chr17:57116881-57116881 (GRCh38) |
| ClinVar | [VCV786656](https://www.ncbi.nlm.nih.gov/clinvar/variation/786656/) |

**All HGVS expressions:** `NC_000017.10:g.55194242G>A`, `NC_000017.11:g.57116881G>A`, `NG_029985.1:g.36690G>A`, `NM_001242902.2:c.2454G>A`, `NM_001242903.2:c.2454G>A`, `NM_001370423.1:c.2454G>A`, `NM_001370424.1:c.2454G>A`, `NM_001370425.1:c.2454G>A`, `NM_001370426.1:c.2454G>A`, `NM_001370427.1:c.2454G>A`, `NM_003488.4:c.2454G>A`

## 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 -8.004, GERP -3.17 — fast-evolving / accelerated position
- CADD: **PHRED 0.225**. 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, Δ0.33 acceptor 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 **3.39%** (afr) · FAF95 3.28% · FAF99 3.24% · 2,544/75,042 in the highest group · 3,038/1,614,186 alleles overall — low-frequency (popmax 3.39%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.39% | 29 |
| Admixed American | 0.298% | 335 |
| Remaining individuals (not grpmax-eligible) | 0.246% | 406 |
| Middle Eastern | 0.115% | 866 |
| European (non-Finnish) | 0.012% | 8,310 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00675% | 14,804 |
| East Asian | 0.00668% | 14,961 |
| South Asian | 0.00659% | 15,181 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,036 |

*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}

**AKAP1** population constraint: LOEUF 0.526, pLI 0.67115, missense-Z 2.489. *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 57.02, 24% of residues very-high.

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

*Describes the biological roles of AKAP1 (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:** AKAP1's established molecular role includes RNA binding.


### Pathways affected {#pathways}

AKAP1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [Mitochondrial calcium ion transport](https://reactome.org/content/detail/R-HSA-8949215) | electronic |

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

**Molecular function:** RNA binding, protein kinase A regulatory subunit binding.

**Biological process:** antiviral innate immune response.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-04-19.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-04-19 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related AKAP1 variant pages (same residue, condition, or type): [AKAP1 p.Pro818Leu](/variant/akap1-p-pro818leu), [AKAP1 c.1976-6A>G](/variant/akap1-c-1976-minus-6a-g), [AKAP1 p.Ala218Thr](/variant/akap1-p-ala218thr), [AKAP1 p.Gly323Ser](/variant/akap1-p-gly323ser), [AKAP1 p.Pro475=](/variant/akap1-p-pro475), [AKAP1 p.Ser330Gly](/variant/akap1-p-ser330gly), [AKAP1 p.Ser388=](/variant/akap1-p-ser388), [AKAP1 p.Thr521Ile](/variant/akap1-p-thr521ile).

### 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 786656). 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.*