# NM_001961.4(EEF2):c.1465dup (p.Glu489fs)

https://sugi.bio/variant/eef2-p-glu489fs

## Summary

**EEF2 p.Glu489fs (c.1465dup)** is classified **Uncertain significance** in EEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-07). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2512201786 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EEF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [EEF2](https://sugi.bio/atlas/gene/EEF2/) |
| Protein change (HGVS p.) | p.Glu489fs |
| Coding change (HGVS c.) | c.1465dup |
| MANE Select transcript | [NM_001961](https://www.ncbi.nlm.nih.gov/nuccore/NM_001961) |
| dbSNP | [rs2512201786](https://www.ncbi.nlm.nih.gov/snp/rs2512201786/) |
| Variant type | Duplication |
| Location | chr19:3979947-3979948 (GRCh38) |
| ClinVar | [VCV2443641](https://www.ncbi.nlm.nih.gov/clinvar/variation/2443641/) |

**All HGVS expressions:** `NC_000019.10:g.3979948dup`, `NC_000019.9:g.3979946dup`, `NG_042274.1:g.10516dup`, `NM_001961.4:c.1465dup`

## 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 7.844, GERP 2.27, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.39, pLI 0.99999), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**EEF2** population constraint: LOEUF 0.39, pLI 0.99999, missense-Z 3.6054. *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):

- **spinocerebellar ataxia type 26** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.97, 66% of residues very-high.

**26 experimental structure(s)** (PDB): [4V6X](https://www.rcsb.org/structure/4V6X), [6D9J](https://www.rcsb.org/structure/6D9J), [6Z6M](https://www.rcsb.org/structure/6Z6M), [6Z6N](https://www.rcsb.org/structure/6Z6N), [8XSX](https://www.rcsb.org/structure/8XSX), [8Y0W](https://www.rcsb.org/structure/8Y0W).

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

*Describes the biological roles of EEF2 (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:** EEF2's established molecular role includes RNA binding. In Reactome, EEF2 is annotated in disease pathway(s) including **Uptake and function of diphtheria toxin**.

**Disease mechanism (Reactome):** EEF2 loss or alteration is curated in [Uptake and function of diphtheria toxin](https://reactome.org/content/detail/R-HSA-5336415).

### Pathways affected {#pathways}

EEF2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Uptake and function of diphtheria toxin](https://reactome.org/content/detail/R-HSA-5336415) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Protein methylation](https://reactome.org/content/detail/R-HSA-8876725) | curated |
| [Peptide chain elongation](https://reactome.org/content/detail/R-HSA-156902) | electronic |
| [Synthesis of diphthamide-EEF2](https://reactome.org/content/detail/R-HSA-5358493) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA binding, translation elongation factor activity, GTPase activity, protein kinase binding, ribosome binding, cadherin binding.

**Biological process:** translational elongation, positive regulation of translation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-07 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related EEF2 variant pages (same residue, condition, or type): [EEF2 p.Gln670fs](/variant/eef2-p-gln670fs), [EEF2 c.1012-2dup](/variant/eef2-c-1012-minus-2dup), [EEF2 p.Asn468fs](/variant/eef2-p-asn468fs), [EEF2 p.Ser82fs](/variant/eef2-p-ser82fs), [EEF2 p.Val24fs](/variant/eef2-p-val24fs), [EEF2 c.1605+115dup](/variant/eef2-c-1605-plus-115dup), [EEF2 c.401-18_401-14dup](/variant/eef2-c-401-minus-18-401-minus-14dup).

### 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 2443641). 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.*