# NM_000117.3(EMD):c.116_143del (p.Phe39fs)

https://sugi.bio/variant/emd-p-phe39fs

## Summary

**EMD p.Phe39fs (c.116_143del)** is classified **Pathogenic** in EMD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-03). No gnomAD frequency available for this variant; Associated with Emery-Dreifuss muscular dystrophy 1, X-linked.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1569552080 · 3 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EMD gene that is considered disease-causing, submitted by 3 submitters, and is linked to Emery-Dreifuss muscular dystrophy 1, X-linked.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026265/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EMD](https://sugi.bio/atlas/gene/EMD/) |
| Protein change (HGVS p.) | p.Phe39fs |
| Coding change (HGVS c.) | c.116_143del |
| MANE Select transcript | [NM_000117](https://www.ncbi.nlm.nih.gov/nuccore/NM_000117) |
| dbSNP | [rs1569552080](https://www.ncbi.nlm.nih.gov/snp/rs1569552080/) |
| Variant type | Deletion |
| Location | chrX:154379721-154379748 (GRCh38) |
| ClinVar | [VCV585847](https://www.ncbi.nlm.nih.gov/clinvar/variation/585847/) |

**All HGVS expressions:** `LRG_745:g.10288_10315del`, `LRG_745t1:c.116_143del`, `NC_000023.10:g.153608083_153608110del`, `NC_000023.11:g.154379723_154379750del`, `NG_008677.1:g.10288_10315del`, `NM_000117.2:c.116_143del28`, `NM_000117.3:c.116_143del`

## Computational & population evidence {#evidence}

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

- **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 7.136, GERP 1.18, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 6**, 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.*

## Protein context {#protein}

Residue **39** lies in the lem domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 61.26, 20% of residues very-high.

**6 experimental structure(s)** (PDB): [1JEI](https://www.rcsb.org/structure/1JEI), [2ODC](https://www.rcsb.org/structure/2ODC), [2ODG](https://www.rcsb.org/structure/2ODG), [6GHD](https://www.rcsb.org/structure/6GHD), [6RPR](https://www.rcsb.org/structure/6RPR), [7NDY](https://www.rcsb.org/structure/7NDY) — incl. mutant structure 6RPR.

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

*Describes the biological roles of EMD (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:** EMD's established molecular role includes actin binding. p.Phe39fs falls in the lem domain.


### Pathways affected {#pathways}

EMD participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Depolymerization of the Nuclear Lamina](https://reactome.org/content/detail/R-HSA-4419969) | curated |
| [Initiation of Nuclear Envelope (NE) Reformation](https://reactome.org/content/detail/R-HSA-2995383) | curated |
| [Nuclear Envelope Breakdown](https://reactome.org/content/detail/R-HSA-2980766) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [Insertion of tail-anchored proteins into the endoplasmic reticulum membrane](https://reactome.org/content/detail/R-HSA-9609523) | electronic |

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

**Molecular function:** actin binding, cadherin binding, beta-tubulin binding.

**Biological process:** positive regulation of protein export from nucleus, negative regulation of fibroblast proliferation, regulation of canonical Wnt signaling pathway, cellular response to growth factor stimulus, nuclear membrane organization, negative regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-03.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2016–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2016-05-19 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-03 |

## Associated conditions {#conditions}

[Emery-Dreifuss muscular dystrophy 1, X-linked](https://sugi.bio/atlas/disease/emery-dreifuss-muscular-dystrophy-1-x-linked/), [X-linked Emery-Dreifuss muscular dystrophy](https://sugi.bio/atlas/disease/x-linked-emery-dreifuss-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Emery-Dreifuss muscular dystrophy 1, X-linked, not provided, X-linked Emery-Dreifuss muscular dystrophy, none provided, SCAPULOPERONEAL SYNDROME, X-LINKED, HUMEROPERONEAL NEUROMUSCULAR DISEASE, EMD-Related Emery-Dreifuss Muscular Dystrophy, X-Linked, Muscular dystrophy, tardive, Dreifuss-Emery type, with contractures, Muscular dystrophy, tardive Emery-Dreifuss type, with contractures.

## Similar variants {#similar}

Related EMD variant pages (same residue, condition, or type): [EMD p.Phe39del](/variant/emd-p-phe39del), [EMD p.Phe39=](/variant/emd-p-phe39), [EMD p.Asn20fs](/variant/emd-p-asn20fs), [EMD p.Leu225fs](/variant/emd-p-leu225fs), [EMD p.Leu84fs](/variant/emd-p-leu84fs), [EMD p.Pro208fs](/variant/emd-p-pro208fs), [EMD p.Ser52fs](/variant/emd-p-ser52fs), [EMD p.Tyr41fs](/variant/emd-p-tyr41fs).

### 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 585847). 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.*