# NM_001961.4(EEF2):c.615C>A (p.Ile205=)

https://sugi.bio/variant/eef2-p-ile205

## Summary

**EEF2 p.Ile205= (c.615C>A)** is classified **Conflicting classifications of pathogenicity** in EEF2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-28). Very rare (popmax 0.00439%, sas).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs375130935 · 2 submitters · very rare (popmax 0.00439%, sas)

## For patients & families {#patients}

This is a change in the EEF2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters.

*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.Ile205= |
| Coding change (HGVS c.) | c.615C>A |
| MANE Select transcript | [NM_001961](https://www.ncbi.nlm.nih.gov/nuccore/NM_001961) |
| dbSNP | [rs375130935](https://www.ncbi.nlm.nih.gov/snp/rs375130935/) |
| Variant type | single nucleotide variant |
| Location | chr19:3982422-3982422 (GRCh38) |
| ClinVar | [VCV1982836](https://www.ncbi.nlm.nih.gov/clinvar/variation/1982836/) |

**All HGVS expressions:** `NC_000019.10:g.3982422G>T`, `NC_000019.9:g.3982420G>T`, `NG_042274.1:g.8042C>A`, `NG_140041.1:g.1050G>T`, `NM_001961.3:c.615C>A`, `NM_001961.4:c.615C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.80) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -5.608, GERP -4.76 — fast-evolving / accelerated position
- CADD: **PHRED 9.712**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.80**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.80**, donor gain **0.00**.
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.05. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00439%** (sas) · FAF95 0.00143% · FAF99 0.000891% · 4/91,084 in the highest group · 11/1,614,036 alleles overall — very rare (popmax 0.00439%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00439% | 22,771 |
| East Asian | 0.00223% | 44,890 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,504 |
| European (non-Finnish) | 0.000424% | 236,008 |

*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 **205** lies in the tr-type g domain.

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. p.Ile205= falls in the tr-type g domain. 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-12-28.

**Submitter consensus:** conflicting (1 likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | likely benign | criteria provided, single submitter | clinical testing | 2024-04-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-28 |

**Reported phenotype names (ClinVar):** not provided, not specified, none provided, AllHighlyPenetrant.

## 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 2026-10-14); 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 1982836). 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.*