# NM_000117.3(EMD):c.711C>T (p.Ile237=)

https://sugi.bio/variant/emd-p-ile237

## Summary

**EMD p.Ile237= (c.711C>T)** is classified **Likely benign** in EMD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-17). Very rare (popmax 0.00176%, sas); Associated with X-linked Emery-Dreifuss muscular dystrophy.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs727503037 · 2 submitters · 1 linked condition · very rare (popmax 0.00176%, sas)

## For patients & families {#patients}

This is a change in the EMD gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to X-linked Emery-Dreifuss muscular dystrophy.

*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, X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | EMD is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Emery-Dreifuss muscular dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Pectus excavatum — Very frequent (99-80%)
- Reduced tendon reflexes — Very frequent (99-80%)
- Joint stiffness — Very frequent (99-80%)
- Myotonia — Very frequent (99-80%)
- Myopathy — Very frequent (99-80%)
- Elevated circulating creatine kinase concentration — Very frequent (99-80%)
- Limb-girdle muscular dystrophy — Very frequent (99-80%)
- Sprengel anomaly — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002102/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.Ile237= |
| Coding change (HGVS c.) | c.711C>T |
| MANE Select transcript | [NM_000117](https://www.ncbi.nlm.nih.gov/nuccore/NM_000117) |
| dbSNP | [rs727503037](https://www.ncbi.nlm.nih.gov/snp/rs727503037/) |
| Variant type | single nucleotide variant |
| Location | chrX:154381143-154381143 (GRCh38) |
| ClinVar | [VCV163405](https://www.ncbi.nlm.nih.gov/clinvar/variation/163405/) |

**All HGVS expressions:** `LRG_745:g.11708C>T`, `LRG_745t1:c.711C>T`, `NC_000023.10:g.153609503C>T`, `NC_000023.11:g.154381143C>T`, `NG_008677.1:g.11708C>T`, `NM_000117.3:c.711C>T`

## 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 0.533, GERP -0.791, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 3.499**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00176%** (sas) · FAF95 0.000325% · FAF99 0.000209% · 1/56,975 in the highest group · 8/1,097,970 alleles overall — very rare (popmax 0.00176%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00176% | 56,975 |
| European (non-Finnish) | 0.000782% | 127,917 |

*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}


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.


### 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-17.

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

**Submission history:** 2 submissions (2013–2024); 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 | 2024-02-17 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2013-05-03 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** X-linked Emery-Dreifuss muscular dystrophy, not specified, Muscular dystrophy, tardive Emery-Dreifuss type, with contractures, AllHighlyPenetrant.

## Similar variants {#similar}

Related EMD variant pages (same residue, condition, or type): [EMD p.Ile237Val](/variant/emd-p-ile237val), [EMD p.Ile237Met](/variant/emd-p-ile237met), [EMD c.187+1G>A](/variant/emd-c-187-plus-1g-a), [EMD c.187+1G>T](/variant/emd-c-187-plus-1g-t), [EMD c.265+1G>A](/variant/emd-c-265-plus-1g-a), [EMD c.266-2A>G](/variant/emd-c-266-minus-2a-g), [EMD c.266-3A>G](/variant/emd-c-266-minus-3a-g), [EMD c.399+1G>T](/variant/emd-c-399-plus-1g-t).

### 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 163405). 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.*