# NM_004247.4(EFTUD2):c.1521G>A (p.Val507=)

https://sugi.bio/variant/eftud2-p-val507

## Summary

**EFTUD2 p.Val507= (c.1521G>A)** is classified **Likely benign** in EFTUD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00834%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs779010188 · 2 submitters · very rare (popmax 0.00834%, amr)

## For patients & families {#patients}

This is a change in the EFTUD2 gene that is classified as likely benign — not considered disease-causing, 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 | [EFTUD2](https://sugi.bio/atlas/gene/EFTUD2/) |
| Protein change (HGVS p.) | p.Val507= |
| Coding change (HGVS c.) | c.1521G>A |
| MANE Select transcript | [NM_004247](https://www.ncbi.nlm.nih.gov/nuccore/NM_004247) |
| dbSNP | [rs779010188](https://www.ncbi.nlm.nih.gov/snp/rs779010188/) |
| Variant type | single nucleotide variant |
| Location | chr17:44862799-44862799 (GRCh38) |
| ClinVar | [VCV1904204](https://www.ncbi.nlm.nih.gov/clinvar/variation/1904204/) |

**All HGVS expressions:** `NC_000017.10:g.42940167C>T`, `NC_000017.11:g.44862799C>T`, `NG_032674.1:g.41827G>A`, `NM_001142605.2:c.1416G>A`, `NM_001258353.2:c.1521G>A`, `NM_001258354.2:c.1491G>A`, `NM_004247.4:c.1521G>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 **donor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.527, GERP -1.47, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 13.55**. 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 **0.00**, acceptor gain **0.00**, donor gain **0.20**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.20**.
- Population frequency (gnomAD v4.1): grpmax **0.00834%** (amr) · FAF95 0.00323% · FAF99 0.00207% · 5/59,978 in the highest group · 33/1,613,928 alleles overall — very rare (popmax 0.00834%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00834% | 11,996 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| European (non-Finnish) | 0.00212% | 47,200 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,046 |

*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 **507** lies in a β-strand.

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. 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-27 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-01 |

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

## Similar variants {#similar}

Related EFTUD2 variant pages (same residue, condition, or type): [EFTUD2 p.Val507Leu](/variant/eftud2-p-val507leu), [EFTUD2 c.1058+1G>A](/variant/eftud2-c-1058-plus-1g-a), [EFTUD2 c.1414-2A>G](/variant/eftud2-c-1414-minus-2a-g), [EFTUD2 c.1607+1G>T](/variant/eftud2-c-1607-plus-1g-t), [EFTUD2 c.1962+1G>A](/variant/eftud2-c-1962-plus-1g-a), [EFTUD2 c.2133-2A>G](/variant/eftud2-c-2133-minus-2a-g), [EFTUD2 c.2562-2A>G](/variant/eftud2-c-2562-minus-2a-g), [EFTUD2 c.702+1G>T](/variant/eftud2-c-702-plus-1g-t).

### 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 1904204). 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.*