# NM_002075.4(GNB3):c.741C>T (p.Asp247=)

https://sugi.bio/variant/gnb3-p-asp247

## Summary

**GNB3 p.Asp247= (c.741C>T)** is classified **Benign/Likely benign** in GNB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-13). Rare (popmax 0.452%, eas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs13306410 · 2 submitters · rare (popmax 0.452%, eas)

## For patients & families {#patients}

This is a change in the GNB3 gene that is classified as benign/likely 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 | [GNB3](https://sugi.bio/atlas/gene/GNB3/) |
| Protein change (HGVS p.) | p.Asp247= |
| Coding change (HGVS c.) | c.741C>T |
| MANE Select transcript | [NM_031299](https://www.ncbi.nlm.nih.gov/nuccore/NM_031299) (variant reported on NM_002075) |
| dbSNP | [rs13306410](https://www.ncbi.nlm.nih.gov/snp/rs13306410/) |
| Variant type | single nucleotide variant |
| Location | chr12:6845627-6845627 (GRCh38) |
| ClinVar | [VCV1167942](https://www.ncbi.nlm.nih.gov/clinvar/variation/1167942/) |

**All HGVS expressions:** `NC_000012.11:g.6954791C>T`, `NC_000012.12:g.6845627C>T`, `NG_009100.2:g.10417C>T`, `NM_001297571.2:c.738C>T`, `NM_001297603.3:c.*1161G>A`, `NM_002075.4:c.741C>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 -13.324, GERP -5.08 — fast-evolving / accelerated position
- CADD: **PHRED 1.732**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.452%** (eas) · FAF95 0.401% · FAF99 0.382% · 203/44,864 in the highest group · 351/1,613,408 alleles overall — rare (popmax 0.452%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.452% | 221 |
| African / African-American | 0.0533% | 1,876 |
| Remaining individuals (not grpmax-eligible) | 0.0288% | 3,472 |
| European (non-Finnish) | 0.00686% | 14,567 |
| South Asian | 0.00659% | 15,181 |
| Admixed American | 0.005% | 20,009 |

*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.*

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-13.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-13 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-19 |

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

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 1167942). 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.*