# NM_021629.4(GNB4):c.265A>G (p.Lys89Glu)

https://sugi.bio/variant/gnb4-p-lys89glu

## Summary

**GNB4 p.Lys89Glu (c.265A>G)** is classified **Pathogenic** in GNB4 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-01-29). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease dominant intermediate F.

**At a glance:** Pathogenic · review: Single submitter · rsID rs387907341 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GNB4 gene that is reported as disease-causing, but on limited review, 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.Lys89Glu |
| Coding change (HGVS c.) | c.265A>G |
| MANE Select transcript | [NM_021629](https://www.ncbi.nlm.nih.gov/nuccore/NM_021629) |
| dbSNP | [rs387907341](https://www.ncbi.nlm.nih.gov/snp/rs387907341/) |
| Variant type | single nucleotide variant |
| Location | chr3:179416495-179416495 (GRCh38) |
| ClinVar | [VCV41941](https://www.ncbi.nlm.nih.gov/clinvar/variation/41941/) |

**All HGVS expressions:** `NC_000003.11:g.179134283T>C`, `NC_000003.12:g.179416495T>C`, `NG_033163.1:g.40089A>G`, `NM_021629.4:c.265A>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.999) — concordant with the pathogenic call
- REVEL 0.5 (indeterminate)
- SaProt LLR -17.591 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.852, GERP 2.15, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 0.75** across the covering region of the MANE Select transcript (179,401,216–179,426,200), spanning 24,984 bp. Chi-square p 4.2e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, T>A, IS in the release and scores Δ0.45 donor loss, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

Residue **89** lies in a UniProt-annotated variant site (in cmtdif; the mutant protein has impaired bradykinin-induced g protein-coupled receptor intracellular signaling compared to the wild-type 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-29.

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

**Submission history:** 2 submissions (2013–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-03-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-29 |

## 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.

## Similar variants {#similar}

Related GNB4 variant pages (same residue, condition, or type): [GNB4 p.Lys89Gln](/variant/gnb4-p-lys89gln), [GNB4 p.Lys89Thr](/variant/gnb4-p-lys89thr), [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).

### 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 41941). 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.*