# NM_001961.4(EEF2):c.1738C>T (p.Arg580Cys)

https://sugi.bio/variant/eef2-p-arg580cys

## Summary

**EEF2 p.Arg580Cys (c.1738C>T)** is classified **Uncertain significance** in EEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-18). AlphaMissense: likely pathogenic (0.8231); Very rare (popmax 0.00147%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00147%, sas)

## 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.Arg580Cys |
| Coding change (HGVS c.) | c.1738C>T |
| MANE Select transcript | [NM_001961](https://www.ncbi.nlm.nih.gov/nuccore/NM_001961) |
| Variant type | single nucleotide variant |
| Location | chr19:3978148-3978148 (GRCh38) |
| ClinVar | [VCV3571833](https://www.ncbi.nlm.nih.gov/clinvar/variation/3571833/) |

**All HGVS expressions:** `NC_000019.10:g.3978148G>A`, `NC_000019.9:g.3978146G>A`, `NG_042274.1:g.12316C>T`, `NM_001961.4:c.1738C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8231)
- REVEL 0.378 (indeterminate)
- SaProt LLR -12.12 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 8.54, GERP 1.28, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.0**. 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 0.12** across the covering region of the MANE Select transcript (3,978,136–3,979,333), spanning 1,197 bp — the region is depleted of missense variation. Chi-square p 1.2e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.71 acceptor gain), 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 **0.00147%** (sas) · FAF95 0.000661% · FAF99 0.000509% · 1/68,042 in the highest group · 17/1,455,786 alleles overall — very rare (popmax 0.00147%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00433% | 23,080 |
| Remaining individuals (not grpmax-eligible) | 0.00357% | 27,974 |
| South Asian (grpmax) | 0.00147% | 68,042 |
| European (non-Finnish) | 0.00118% | 84,422 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **580** lies in a β-strand.

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 2024-06-18.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-18 |

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

## Similar variants {#similar}

Related EEF2 variant pages (same residue, condition, or type): [EEF2 p.Ala237Thr](/variant/eef2-p-ala237thr), [EEF2 p.Ala238Thr](/variant/eef2-p-ala238thr), [EEF2 p.Ala338Gly](/variant/eef2-p-ala338gly), [EEF2 p.Ala624Thr](/variant/eef2-p-ala624thr), [EEF2 p.Ala808Val](/variant/eef2-p-ala808val), [EEF2 p.Arg633His](/variant/eef2-p-arg633his), [EEF2 p.Arg647His](/variant/eef2-p-arg647his), [EEF2 p.Arg726Trp](/variant/eef2-p-arg726trp).

### 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 3571833). 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.*