# NM_005273.4(GNB2):c.265A>G (p.Lys89Glu)

https://sugi.bio/variant/gnb2-p-lys89glu

## Summary

**GNB2 p.Lys89Glu (c.265A>G)** is classified **Pathogenic** in GNB2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-03). AlphaMissense: likely pathogenic (0.9988); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia and dysmorphic facies.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2131350514 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GNB2 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to neurodevelopmental disorder with hypotonia and dysmorphic facies.

*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 | [GNB2](https://sugi.bio/atlas/gene/GNB2/) |
| Protein change (HGVS p.) | p.Lys89Glu |
| Coding change (HGVS c.) | c.265A>G |
| MANE Select transcript | [NM_005273](https://www.ncbi.nlm.nih.gov/nuccore/NM_005273) |
| dbSNP | [rs2131350514](https://www.ncbi.nlm.nih.gov/snp/rs2131350514/) |
| Variant type | single nucleotide variant |
| Location | chr7:100677413-100677413 (GRCh38) |
| ClinVar | [VCV1217306](https://www.ncbi.nlm.nih.gov/clinvar/variation/1217306/) |

**All HGVS expressions:** `NC_000007.13:g.100275036A>G`, `NC_000007.14:g.100677413A>G`, `NM_005273.4:c.265A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9988) — concordant with the pathogenic call
- REVEL 0.46 (indeterminate)
- SaProt LLR -17.18 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 11.29, GERP 4.92, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 0.60** across the covering region of the MANE Select transcript (100,676,266–100,678,798), spanning 2,532 bp. Chi-square p 8.1e-18. 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). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. 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. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. 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, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GNB2 (488 scored positions, the nearest 3 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *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}

**GNB2** population constraint: LOEUF 0.372, pLI 0.99977, missense-Z 3.0831. *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):

- **complex neurodevelopmental disorder** — Moderate (AD)

## Protein context {#protein}

Residue **89** lies in a UniProt-annotated variant site (in nedhydf).

AlphaFold model confidence (whole protein): pLDDT 96.89, 97% of residues very-high.

**1 experimental structure(s)** (PDB): [9AVL](https://www.rcsb.org/structure/9AVL).

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

*Describes the biological roles of GNB2 (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:** GNB2's established molecular role includes protein-containing complex binding. In Reactome, GNB2 is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**.

**Disease mechanism (Reactome):** GNB2 loss or alteration is curated in [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821).

### Pathways affected {#pathways}

GNB2 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, GTPase binding.

**Biological process:** regulation of potassium ion transmembrane transport.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-03.

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

**Submission history:** 2 submissions (2021–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Pathogenic | criteria provided, single submitter | clinical testing | 2021-08-03 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2022-04-25 |

## Associated conditions {#conditions}

[neurodevelopmental disorder with hypotonia and dysmorphic facies](https://sugi.bio/atlas/disease/neurodevelopmental-disorder-with-hypotonia-and-dysmorphic-facies/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder with hypotonia and dysmorphic facies.

## Same-residue context {#hotspot}

Residue **89** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GNB2 p.Lys89Thr](/variant/gnb2-p-lys89thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GNB2 variant pages (same residue, condition, or type): [GNB2 p.Lys89Thr](/variant/gnb2-p-lys89thr), [GNB2 p.Ala73Thr](/variant/gnb2-p-ala73thr), [GNB2 p.Asn268Ile](/variant/gnb2-p-asn268ile), [GNB2 p.Asp76Gly](/variant/gnb2-p-asp76gly), [GNB2 p.Gly77Trp](/variant/gnb2-p-gly77trp), [GNB2 p.Arg280Ser](/variant/gnb2-p-arg280ser), [GNB2 p.Ile80Asn](/variant/gnb2-p-ile80asn), [GNB2 p.Leu262Phe](/variant/gnb2-p-leu262phe).

### 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 1217306). 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.*