# NM_002074.5(GNB1):c.265A>G (p.Lys89Glu)

https://sugi.bio/variant/gnb1-p-lys89glu

## Summary

**GNB1 p.Lys89Glu (c.265A>G)** is classified **Conflicting classifications of pathogenicity** in GNB1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-01). AlphaMissense: likely pathogenic (0.9989); No allele count reported in gnomAD v4.1 (AN 1,595,622); Associated with intellectual disability, autosomal dominant 42.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,595,622)

## For patients & families {#patients}

This is a change in the GNB1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to intellectual disability, autosomal dominant 42.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018501/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GNB1](https://sugi.bio/atlas/gene/GNB1/) |
| Protein change (HGVS p.) | p.Lys89Glu |
| Coding change (HGVS c.) | c.265A>G |
| MANE Select transcript | [NM_002074](https://www.ncbi.nlm.nih.gov/nuccore/NM_002074) |
| Variant type | single nucleotide variant |
| Location | chr1:1806477-1806477 (GRCh38) |
| ClinVar | [VCV3897833](https://www.ncbi.nlm.nih.gov/clinvar/variation/3897833/) |

**All HGVS expressions:** `NC_000001.10:g.1737916T>C`, `NC_000001.11:g.1806477T>C`, `NG_047052.1:g.89641A>G`, `NM_001282538.2:c.-36A>G`, `NM_001282539.2:c.265A>G`, `NM_002074.5:c.265A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9989)
- REVEL 0.543 (indeterminate)
- SaProt LLR -16.771 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.722, GERP 2.61, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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 0.37** across the covering region of the MANE Select transcript (1,787,334–1,815,835), spanning 28,501 bp. Chi-square p 7e-38. 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: **no allele count reported in gnomAD v4.1 (AN 1,595,622)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**GNB1** population constraint: LOEUF 0.222, pLI 0.9976, missense-Z 3.4867; ClinGen dosage — haploinsufficiency 1/3, 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):

- **intellectual disability, autosomal dominant 42** — Definitive (AD)

## Protein context {#protein}

Residue **89** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 97.04, 97% of residues very-high.

**1043 experimental structure(s)** (PDB): [10JA](https://www.rcsb.org/structure/10JA), [10JB](https://www.rcsb.org/structure/10JB), [12IZ](https://www.rcsb.org/structure/12IZ), [12JA](https://www.rcsb.org/structure/12JA), [20YC](https://www.rcsb.org/structure/20YC), [20ZC](https://www.rcsb.org/structure/20ZC) — incl. mutant structure 7Y67.

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

*Describes the biological roles of GNB1 (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:** GNB1's established molecular role includes GTPase activity. In Reactome, GNB1 is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**.

**Disease mechanism (Reactome):** GNB1 loss or alteration is curated in [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821).

### Pathways affected {#pathways}

GNB1 participates in **34 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 |
| [Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)](https://reactome.org/content/detail/R-HSA-381771) | 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 |
| [Activation of the phototransduction cascade](https://reactome.org/content/detail/R-HSA-2485179) | 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) | electronic |
| [Olfactory Signaling Pathway](https://reactome.org/content/detail/R-HSA-381753) | electronic |
| [Prostacyclin signalling through prostacyclin receptor](https://reactome.org/content/detail/R-HSA-392851) | electronic |
| [Sensory perception of sweet, bitter, and umami (glutamate) taste](https://reactome.org/content/detail/R-HSA-9717207) | 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 activity, protein-containing complex binding, GTPase binding.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-01-01.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center of Human Genetics, Hôpital Erasme | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-01 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-05 |

## Associated conditions {#conditions}

[intellectual disability, autosomal dominant 42](https://sugi.bio/atlas/disease/intellectual-disability-autosomal-dominant-42/).

**Reported phenotype names (ClinVar):** Intellectual disability, autosomal dominant 42, not provided, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 42, GNB1 Encephalopathy, Global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome, none provided.

## Same-residue context {#hotspot}

Residue **89** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GNB1 p.Lys89Arg](/variant/gnb1-p-lys89arg). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GNB1 variant pages (same residue, condition, or type): [GNB1 p.Lys89Met](/variant/gnb1-p-lys89met), [GNB1 p.Lys89Arg](/variant/gnb1-p-lys89arg), [GNB1 c.498-2A>G](/variant/gnb1-c-498-minus-2a-g), [GNB1 p.Ala73Ser](/variant/gnb1-p-ala73ser), [GNB1 p.Ala73Thr](/variant/gnb1-p-ala73thr), [GNB1 p.Ala92Thr](/variant/gnb1-p-ala92thr), [GNB1 p.Asp118Gly](/variant/gnb1-p-asp118gly), [GNB1 p.Asp118His](/variant/gnb1-p-asp118his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3897833). 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.*