# NM_004247.4(EFTUD2):c.158del (p.Pro53fs)

https://sugi.bio/variant/eftud2-p-pro53fs

## Summary

**EFTUD2 p.Pro53fs (c.158del)** is classified **Pathogenic** in EFTUD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2145558864 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EFTUD2 gene that is reported as disease-causing, but on limited review, 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 | [EFTUD2](https://sugi.bio/atlas/gene/EFTUD2/) |
| Protein change (HGVS p.) | p.Pro53fs |
| Coding change (HGVS c.) | c.158del |
| MANE Select transcript | [NM_004247](https://www.ncbi.nlm.nih.gov/nuccore/NM_004247) |
| dbSNP | [rs2145558864](https://www.ncbi.nlm.nih.gov/snp/rs2145558864/) |
| Variant type | Deletion |
| Location | chr17:44886698-44886698 (GRCh38) |
| ClinVar | [VCV1431432](https://www.ncbi.nlm.nih.gov/clinvar/variation/1431432/) |

**All HGVS expressions:** `NC_000017.10:g.42964068del`, `NC_000017.11:g.44886700del`, `NG_032674.1:g.17928del`, `NM_001142605.2:c.53del`, `NM_001258353.2:c.158del`, `NM_001258354.2:c.158del`, `NM_004247.4:c.158del`

## 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 -3.953, GERP -3.7 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.145, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 28**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**EFTUD2** population constraint: LOEUF 0.145, pLI 1, missense-Z 5.3671; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **mandibulofacial dysostosis-microcephaly syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **53** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 89.94, 76% of residues very-high.

**72 experimental structure(s)** (PDB): [3JCR](https://www.rcsb.org/structure/3JCR), [5MQF](https://www.rcsb.org/structure/5MQF), [5O9Z](https://www.rcsb.org/structure/5O9Z), [5XJC](https://www.rcsb.org/structure/5XJC), [5YZG](https://www.rcsb.org/structure/5YZG), [5Z56](https://www.rcsb.org/structure/5Z56) — incl. mutant structure 8CH6.

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

*Describes the biological roles of EFTUD2 (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:** EFTUD2's established molecular role includes RNA binding. p.Pro53fs falls in the disordered region. In Reactome, EFTUD2 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** EFTUD2 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

EFTUD2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |
| [mRNA Splicing - Minor Pathway](https://reactome.org/content/detail/R-HSA-72165) | curated |

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

**Molecular function:** RNA binding.

**Biological process:** mRNA splicing, via spliceosome.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-09.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-09 |

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

## Similar variants {#similar}

Related EFTUD2 variant pages (same residue, condition, or type): [EFTUD2 p.Pro53Arg](/variant/eftud2-p-pro53arg), [EFTUD2 p.Pro53His](/variant/eftud2-p-pro53his), [EFTUD2 p.Pro53Ser](/variant/eftud2-p-pro53ser), [EFTUD2 c.2562-2_2562-1del](/variant/eftud2-c-2562-minus-2-2562-minus-1del), [EFTUD2 c.2562-2del](/variant/eftud2-c-2562-minus-2del), [EFTUD2 c.702+1del](/variant/eftud2-c-702-plus-1del), [EFTUD2 p.Leu190fs](/variant/eftud2-p-leu190fs), [EFTUD2 p.Leu474fs](/variant/eftud2-p-leu474fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1431432). 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.*