# NM_001958.5(EEF1A2):c.1267C>T (p.Arg423Cys)

https://sugi.bio/variant/eef1a2-p-arg423cys

## Summary

**EEF1A2 p.Arg423Cys (c.1267C>T)** is classified **Pathogenic/Likely pathogenic** in EEF1A2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-09-07). AlphaMissense: likely pathogenic (0.9994); No allele count reported in gnomAD v4.1 (AN 1,451,526); Associated with developmental and epileptic encephalopathy, 33.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs886039346 · 5 submitters · 1 linked condition · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,451,526)

## For patients & families {#patients}

This is a change in the EEF1A2 gene that is considered likely disease-causing, submitted by 5 submitters, and is linked to developmental and epileptic encephalopathy, 33.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | EEF1A2 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Non-specific early-onset epileptic encephalopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Encephalopathy — Very frequent (99-80%)
- Delayed speech and language development — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)
- Hyporeflexia — Frequent (79-30%)
- Generalized hypotonia — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016106/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EEF1A2](https://sugi.bio/atlas/gene/EEF1A2/) |
| Protein change (HGVS p.) | p.Arg423Cys |
| Coding change (HGVS c.) | c.1267C>T |
| MANE Select transcript | [NM_001958](https://www.ncbi.nlm.nih.gov/nuccore/NM_001958) |
| dbSNP | [rs886039346](https://www.ncbi.nlm.nih.gov/snp/rs886039346/) |
| Variant type | single nucleotide variant |
| Location | chr20:63488423-63488423 (GRCh38) |
| ClinVar | [VCV265111](https://www.ncbi.nlm.nih.gov/clinvar/variation/265111/) |

**All HGVS expressions:** `NC_000020.10:g.62119776G>A`, `NC_000020.11:g.63488423G>A`, `NG_034083.1:g.15893C>T`, `NM_001958.5:c.1267C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9994) — concordant with the pathogenic call
- REVEL 0.318 (indeterminate)
- SaProt LLR -14.437 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 11.415, GERP 0.638, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.7**. 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 0.27** across the covering region of the MANE Select transcript (63,488,410–63,493,232), spanning 4,822 bp — the region is depleted of missense variation. Chi-square p 4e-36. 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, Δ0.83 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: **no allele count reported in gnomAD v4.1 (AN 1,451,526)** — 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}

**EEF1A2** population constraint: LOEUF 0.314, pLI 0.99995, missense-Z 6.0642; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **423** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 88.70, 59% of residues very-high.

**2 experimental structure(s)** (PDB): [8B6Z](https://www.rcsb.org/structure/8B6Z), [3C5J](https://www.rcsb.org/structure/3C5J).

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

*Describes the biological roles of EEF1A2 (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:** EEF1A2's established molecular role includes protein kinase binding.


### Pathways affected {#pathways}

EEF1A2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Eukaryotic Translation Elongation](https://reactome.org/content/detail/R-HSA-156842) | electronic |

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

**Molecular function:** protein kinase binding.

**Biological process:** positive regulation of lipid kinase activity.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-09-07.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic, 1 not provided).

**Submission history:** 5 submissions (2017–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2020-12-31 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-09-21 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-07 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-01 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 33](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-33/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 33, not provided, Inborn genetic diseases, Epileptic encephalopathy, early infantile, 33, none provided.

## Similar variants {#similar}

Related EEF1A2 variant pages (same residue, condition, or type): [EEF1A2 p.Arg423=](/variant/eef1a2-p-arg423), [EEF1A2 p.Arg423Gln](/variant/eef1a2-p-arg423gln), [EEF1A2 p.Arg266Trp](/variant/eef1a2-p-arg266trp), [EEF1A2 p.Arg69Cys](/variant/eef1a2-p-arg69cys), [EEF1A2 p.Asp91Asn](/variant/eef1a2-p-asp91asn), [EEF1A2 p.Asp97Asn](/variant/eef1a2-p-asp97asn), [EEF1A2 p.Glu122Lys](/variant/eef1a2-p-glu122lys), [EEF1A2 p.Glu124Lys](/variant/eef1a2-p-glu124lys).

### 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 265111). 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.*