# NM_013302.5(EEF2K):c.1343G>A (p.Arg448Gln)

https://sugi.bio/variant/eef2k-p-arg448gln

## Summary

**EEF2K p.Arg448Gln (c.1343G>A)** is classified **Uncertain significance** in EEF2K (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-26). AlphaMissense: likely benign (0.1114); Ultra-rare (popmax 0.0223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs751431906 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0223%, eas)

## For patients & families {#patients}

This is a change in the EEF2K 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 | [EEF2K](https://sugi.bio/atlas/gene/EEF2K/) |
| Protein change (HGVS p.) | p.Arg448Gln |
| Coding change (HGVS c.) | c.1343G>A |
| MANE Select transcript | [NM_013302](https://www.ncbi.nlm.nih.gov/nuccore/NM_013302) |
| dbSNP | [rs751431906](https://www.ncbi.nlm.nih.gov/snp/rs751431906/) |
| Variant type | single nucleotide variant |
| Location | chr16:22263153-22263153 (GRCh38) |
| ClinVar | [VCV2298000](https://www.ncbi.nlm.nih.gov/clinvar/variation/2298000/) |

**All HGVS expressions:** `NC_000016.10:g.22263153G>A`, `NC_000016.9:g.22274474G>A`, `NM_013302.5:c.1343G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1114)
- REVEL 0.182 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.425 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.46, GERP 0.364, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.3**. 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 0.96** across the covering region of the MANE Select transcript (22,225,730–22,283,993), spanning 58,263 bp. Chi-square p 0.22. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.20**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.20**.
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.08. 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 **0.0223%** (eas) · FAF95 0.012% · FAF99 0.00918% · 10/44,810 in the highest group · 20/1,612,470 alleles overall — ultra-rare (popmax 0.0223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0223% | 4,481 |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,183 |
| South Asian | 0.0022% | 45,442 |
| Admixed American | 0.00167% | 59,844 |
| African / African-American | 0.00134% | 74,854 |
| European (non-Finnish) | 0.000339% | 294,809 |

*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}

**EEF2K** population constraint: LOEUF 0.896, pLI 3.9516e-17, missense-Z 0.7747. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **448** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.36, 46% of residues very-high.

**10 experimental structure(s)** (PDB): [5J8H](https://www.rcsb.org/structure/5J8H), [5KS5](https://www.rcsb.org/structure/5KS5), [6NX4](https://www.rcsb.org/structure/6NX4), [7SHQ](https://www.rcsb.org/structure/7SHQ), [8FNY](https://www.rcsb.org/structure/8FNY), [8FO6](https://www.rcsb.org/structure/8FO6).

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

*Describes the biological roles of EEF2K (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:** EEF2K's established molecular role includes elongation factor-2 kinase activity. p.Arg448Gln falls in the disordered region.


### Pathways affected {#pathways}

EEF2K participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [mTORC1-mediated signalling](https://reactome.org/content/detail/R-HSA-166208) | curated |

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

**Molecular function:** elongation factor-2 kinase activity, calmodulin binding.

**Biological process:** protein autophosphorylation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-26 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related EEF2K variant pages (same residue, condition, or type): [EEF2K p.Arg448Gly](/variant/eef2k-p-arg448gly), [EEF2K p.Ala158Asp](/variant/eef2k-p-ala158asp), [EEF2K p.Ala164Thr](/variant/eef2k-p-ala164thr), [EEF2K p.Ala169Val](/variant/eef2k-p-ala169val), [EEF2K p.Ala306Val](/variant/eef2k-p-ala306val), [EEF2K p.Ala313Asp](/variant/eef2k-p-ala313asp), [EEF2K p.Ala558Thr](/variant/eef2k-p-ala558thr), [EEF2K p.Ala617Val](/variant/eef2k-p-ala617val).

### 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 2298000). 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.*