# NM_016194.4(GNB5):c.739C>G (p.Pro247Ala)

https://sugi.bio/variant/gnb5-p-pro247ala

## Summary

**GNB5 p.Pro247Ala (c.739C>G)** is classified **Uncertain significance** in GNB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: ambiguous (0.3974); Very rare (popmax 0.00525%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00525%, nfe)

## For patients & families {#patients}

This is a change in the GNB5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [GNB5](https://sugi.bio/atlas/gene/GNB5/) |
| Protein change (HGVS p.) | p.Pro247Ala |
| Coding change (HGVS c.) | c.739C>G |
| MANE Select transcript | [NM_016194](https://www.ncbi.nlm.nih.gov/nuccore/NM_016194) |
| Variant type | single nucleotide variant |
| Location | chr15:52135645-52135645 (GRCh38) |
| ClinVar | [VCV3520949](https://www.ncbi.nlm.nih.gov/clinvar/variation/3520949/) |

**All HGVS expressions:** `NC_000015.10:g.52135645G>C`, `NC_000015.9:g.52427842G>C`, `NG_052868.1:g.60724C>G`, `NG_052868.2:g.60747C>G`, `NM_001379343.1:c.457C>G`, `NM_006578.4:c.613C>G`, `NM_016194.4:c.739C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3974) — no call either way
- REVEL 0.652 (pathogenic-leaning)
- SaProt LLR -11.406 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 9.944, GERP 1.13, phastCons 1 — highly conserved
- CADD: **PHRED 28.8**. 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 (52,122,760–52,184,676), spanning 61,916 bp. Chi-square p 0.083. 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 **0.00525%** (nfe) · FAF95 0.00418% · FAF99 0.0038% · 62/1,179,866 in the highest group · 64/1,613,610 alleles overall — very rare (popmax 0.00525%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00525% | 19,030 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,234 |

*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}

**GNB5** population constraint: LOEUF 1.155, pLI 1.1316e-05, missense-Z 0.23735. *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 93.92, 83% of residues very-high.

**37 experimental structure(s)** (PDB): [7EWP](https://www.rcsb.org/structure/7EWP), [7EWR](https://www.rcsb.org/structure/7EWR), [8SG8](https://www.rcsb.org/structure/8SG8), [8SG9](https://www.rcsb.org/structure/8SG9), [8SGC](https://www.rcsb.org/structure/8SGC), [8SGL](https://www.rcsb.org/structure/8SGL).

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

*Describes the biological roles of GNB5 (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:** GNB5's established molecular role includes GTPase activator activity. In Reactome, GNB5 is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**.

**Disease mechanism (Reactome):** GNB5 loss or alteration is curated in [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821).

### Pathways affected {#pathways}

GNB5 participates in **29 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821) | curated |
| [ADP signalling through P2Y purinoceptor 12](https://reactome.org/content/detail/R-HSA-392170) | curated |
| [Activation of G protein gated Potassium channels](https://reactome.org/content/detail/R-HSA-1296041) | curated |
| [Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding](https://reactome.org/content/detail/R-HSA-6814122) | curated |
| [Extra-nuclear estrogen signaling](https://reactome.org/content/detail/R-HSA-9009391) | curated |
| [G alpha (12/13) signalling events](https://reactome.org/content/detail/R-HSA-416482) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |
| [G alpha (z) signalling events](https://reactome.org/content/detail/R-HSA-418597) | curated |
| [G beta:gamma signalling through BTK](https://reactome.org/content/detail/R-HSA-8964315) | curated |
| [G beta:gamma signalling through CDC42](https://reactome.org/content/detail/R-HSA-8964616) | curated |
| [G beta:gamma signalling through PI3Kgamma](https://reactome.org/content/detail/R-HSA-392451) | curated |
| [G beta:gamma signalling through PLC beta](https://reactome.org/content/detail/R-HSA-418217) | curated |
| [G-protein activation](https://reactome.org/content/detail/R-HSA-202040) | curated |
| [GPER1 signaling](https://reactome.org/content/detail/R-HSA-9634597) | curated |
| [Glucagon-type ligand receptors](https://reactome.org/content/detail/R-HSA-420092) | 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 |
| [Inhibition  of voltage gated Ca2+ channels via Gbeta/gamma subunits](https://reactome.org/content/detail/R-HSA-997272) | curated |
| [Presynaptic function of Kainate receptors](https://reactome.org/content/detail/R-HSA-500657) | curated |
| [Thromboxane signalling through TP receptor](https://reactome.org/content/detail/R-HSA-428930) | curated |
| [Vasopressin regulates renal water homeostasis via Aquaporins](https://reactome.org/content/detail/R-HSA-432040) | curated |
| [ADP signalling through P2Y purinoceptor 1](https://reactome.org/content/detail/R-HSA-418592) | electronic |
| [Adrenaline,noradrenaline inhibits insulin secretion](https://reactome.org/content/detail/R-HSA-400042) | electronic |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | electronic |
| [Glucagon-like Peptide-1 (GLP1) regulates insulin secretion](https://reactome.org/content/detail/R-HSA-381676) | electronic |
| [Inactivation, recovery and regulation of the phototransduction cascade](https://reactome.org/content/detail/R-HSA-2514859) | other |
| [Prostacyclin signalling through prostacyclin receptor](https://reactome.org/content/detail/R-HSA-392851) | electronic |
| [Thrombin signalling through proteinase activated receptors (PARs)](https://reactome.org/content/detail/R-HSA-456926) | electronic |

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

**Molecular function:** GTPase activator activity, G-protein gamma-subunit binding, protein-folding chaperone binding.

**Biological process:** G protein-coupled receptor signaling pathway, G protein-coupled dopamine receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-03.

**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 | 2024-12-03 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related GNB5 variant pages (same residue, condition, or type): [GNB5 p.Ala142Thr](/variant/gnb5-p-ala142thr), [GNB5 p.Asn345Ser](/variant/gnb5-p-asn345ser), [GNB5 p.Phe364Leu](/variant/gnb5-p-phe364leu), [GNB5 p.Ser292Thr](/variant/gnb5-p-ser292thr), [GNB5 p.Val274Met](/variant/gnb5-p-val274met), [GNB5 p.Val370Ile](/variant/gnb5-p-val370ile), [GNB5 p.Trp222Ter](/variant/gnb5-p-trp222ter), [GNB5 c.375+3A>G](/variant/gnb5-c-375-plus-3a-g).

### 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 2026-10-14); 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 3520949). 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.*