# NM_021629.4(GNB4):c.723C>T (p.Phe241=)

https://sugi.bio/variant/gnb4-p-phe241

## Summary

**GNB4 p.Phe241= (c.723C>T)** is classified **Likely benign** in GNB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-24). Ultra-rare (popmax 0.0165%, mid); Associated with Charcot-Marie-Tooth disease dominant intermediate F.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs752815541 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the GNB4 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Charcot-Marie-Tooth disease dominant intermediate F.

*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) | All ages |
| Diagnostic panels | GNB4 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009206/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GNB4](https://sugi.bio/atlas/gene/GNB4/) |
| Protein change (HGVS p.) | p.Phe241= |
| Coding change (HGVS c.) | c.723C>T |
| MANE Select transcript | [NM_021629](https://www.ncbi.nlm.nih.gov/nuccore/NM_021629) |
| dbSNP | [rs752815541](https://www.ncbi.nlm.nih.gov/snp/rs752815541/) |
| Variant type | single nucleotide variant |
| Location | chr3:179405383-179405383 (GRCh38) |
| ClinVar | [VCV1631004](https://www.ncbi.nlm.nih.gov/clinvar/variation/1631004/) |

**All HGVS expressions:** `NC_000003.11:g.179123171G>A`, `NC_000003.12:g.179405383G>A`, `NG_033163.1:g.51201C>T`, `NM_021629.4:c.723C>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 1.321, GERP -4.29, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 9.671**. 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 loss), 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 **0.0165%** (mid) · FAF95 0.00816% · FAF99 0.00634% · 1/6,074 in the highest group · 32/1,612,548 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,074 |
| African / African-American | 0.0147% | 6,808 |
| Remaining individuals (not grpmax-eligible) | 0.00961% | 10,407 |
| European (non-Finnish) | 0.00119% | 84,211 |

*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}

**GNB4** population constraint: LOEUF 0.863, pLI 0.0053098, missense-Z 1.8036; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Charcot-Marie-Tooth disease** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 97.14, 97% of residues very-high.

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

*Describes the biological roles of GNB4 (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:** GNB4's established molecular role includes protein-containing complex binding. In Reactome, GNB4 is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**.

**Disease mechanism (Reactome):** GNB4 loss or alteration is curated in [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821).

### Pathways affected {#pathways}

GNB4 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 signaling in metabolic regulation](https://reactome.org/content/detail/R-HSA-163359) | 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 |
| [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:** protein-containing complex binding.

**Biological process:** substantia nigra development.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-24.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-24 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease dominant intermediate F](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-dominant-intermediate-f/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease dominant intermediate F, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related GNB4 variant pages (same residue, condition, or type): [GNB4 p.Gly77Arg](/variant/gnb4-p-gly77arg), [GNB4 p.Lys57Glu](/variant/gnb4-p-lys57glu), [GNB4 c.497+1G>C](/variant/gnb4-c-497-plus-1g-c), [GNB4 p.Arg137Ter](/variant/gnb4-p-arg137ter), [GNB4 p.Arg15Trp](/variant/gnb4-p-arg15trp), [GNB4 p.Arg214Ter](/variant/gnb4-p-arg214ter), [GNB4 p.Arg22Gln](/variant/gnb4-p-arg22gln), [GNB4 p.Arg251Gln](/variant/gnb4-p-arg251gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1631004). 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.*