# NM_001164760.2(PRKAR1B):c.917G>A (p.Arg306Gln)

https://sugi.bio/variant/prkar1b-p-arg306gln

## Summary

**PRKAR1B p.Arg306Gln (c.917G>A)** is classified **Pathogenic** in PRKAR1B (ClinVar, Single submitter, 2 submitters; last evaluated 2024-12-31). AlphaMissense: likely benign (0.2498); Very rare (popmax 0.00194%, amr); Associated with Marbach-Schaaf neurodevelopmental syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs866622752 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00194%, amr)

## For patients & families {#patients}

This is a change in the PRKAR1B gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 2 submitters, and is linked to Marbach-Schaaf neurodevelopmental 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | PRKAR1B is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027395/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRKAR1B](https://sugi.bio/atlas/gene/PRKAR1B/) |
| Protein change (HGVS p.) | p.Arg306Gln |
| Coding change (HGVS c.) | c.917G>A |
| MANE Select transcript | [NM_001164760](https://www.ncbi.nlm.nih.gov/nuccore/NM_001164760) |
| dbSNP | [rs866622752](https://www.ncbi.nlm.nih.gov/snp/rs866622752/) |
| Variant type | single nucleotide variant |
| Location | chr7:551445-551445 (GRCh38) |
| ClinVar | [VCV2444586](https://www.ncbi.nlm.nih.gov/clinvar/variation/2444586/) |

**All HGVS expressions:** `NC_000007.13:g.591082C>T`, `NC_000007.14:g.551445C>T`, `NG_042811.1:g.181232G>A`, `NM_001164758.2:c.917G>A`, `NM_001164759.1:c.917G>A`, `NM_001164760.2:c.917G>A`, `NM_001164761.2:c.917G>A`, `NM_001164762.2:c.917G>A`, `NM_002735.3:c.917G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.2498) — ⚠ discordant with the pathogenic call
- REVEL 0.44 (indeterminate)
- SaProt LLR -7.083 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 7.388, GERP 1.99, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.2**. 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 0.92** across the covering region of the MANE Select transcript (550,433–579,282), spanning 28,849 bp. Chi-square p 0.35. 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 **0.00194%** (amr) · FAF95 8.1e-05% · FAF99 5.5e-05% · 1/51,470 in the highest group · 6/1,558,612 alleles overall — very rare (popmax 0.00194%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00194% | 51,470 |
| Remaining individuals (not grpmax-eligible) | 0.00166% | 60,376 |
| European (non-Finnish) | 0.000348% | 287,766 |

*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}

**PRKAR1B** population constraint: LOEUF 0.686, pLI 0.0079626, missense-Z 1.3997. *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 87.24, 60% of residues very-high.

**3 experimental structure(s)** (PDB): [4DIN](https://www.rcsb.org/structure/4DIN), [4F9K](https://www.rcsb.org/structure/4F9K), [9O7V](https://www.rcsb.org/structure/9O7V).

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

*Describes the biological roles of PRKAR1B (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:** PRKAR1B's established molecular role includes cAMP-dependent protein kinase inhibitor activity. In Reactome, PRKAR1B is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**, **FCGR3A-mediated IL10 synthesis**.

**Disease mechanism (Reactome):** PRKAR1B 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).

### Pathways affected {#pathways}

PRKAR1B participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821) | other |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | other |
| [CREB1 phosphorylation through the activation of Adenylate Cyclase](https://reactome.org/content/detail/R-HSA-442720) | other |
| [DARPP-32 events](https://reactome.org/content/detail/R-HSA-180024) | other |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | other |
| [GPER1 signaling](https://reactome.org/content/detail/R-HSA-9634597) | other |
| [Glucagon-like Peptide-1 (GLP1) regulates insulin secretion](https://reactome.org/content/detail/R-HSA-381676) | other |
| [Hedgehog 'off' state](https://reactome.org/content/detail/R-HSA-5610787) | other |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | other |
| [PKA activation](https://reactome.org/content/detail/R-HSA-163615) | other |
| [PKA activation in glucagon signalling](https://reactome.org/content/detail/R-HSA-164378) | other |
| [Vasopressin regulates renal water homeostasis via Aquaporins](https://reactome.org/content/detail/R-HSA-432040) | other |

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

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

**Biological process:** negative regulation of cAMP/PKA signal transduction.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-31.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Uncertain significance | no assertion criteria provided | clinical testing | 2024-02-08 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-31 |

## Associated conditions {#conditions}

[Marbach-Schaaf neurodevelopmental syndrome](https://sugi.bio/atlas/disease/marbach-schaaf-neurodevelopmental-syndrome/).

**Reported phenotype names (ClinVar):** not provided, Marbach-Schaaf neurodevelopmental syndrome, none provided.

## Similar variants {#similar}

Related PRKAR1B variant pages (same residue, condition, or type): [PRKAR1B p.Arg335Trp](/variant/prkar1b-p-arg335trp), [PRKAR1B p.Arg305Cys](/variant/prkar1b-p-arg305cys), [PRKAR1B p.Trp190Ter](/variant/prkar1b-p-trp190ter), [PRKAR1B p.Ala270Val](/variant/prkar1b-p-ala270val), [PRKAR1B p.Ala336Val](/variant/prkar1b-p-ala336val), [PRKAR1B p.Arg357Cys](/variant/prkar1b-p-arg357cys), [PRKAR1B p.Glu196Lys](/variant/prkar1b-p-glu196lys), [PRKAR1B p.Glu202Asp](/variant/prkar1b-p-glu202asp).

### 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 2444586). 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.*