# NM_000117.3(EMD):c.215A>T (p.Asp72Val)

https://sugi.bio/variant/emd-p-asp72val

## Summary

**EMD p.Asp72Val (c.215A>T)** is classified **Uncertain significance** in EMD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-11). AlphaMissense: ambiguous (0.3479); Very rare (popmax 0.000894%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs794729021 · 6 submitters · 3 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.000894%, nfe)

## For patients & families {#patients}

This is a change in the EMD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 6 submitters, and is linked to Cardiovascular phenotype.

*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 | [EMD](https://sugi.bio/atlas/gene/EMD/) |
| Protein change (HGVS p.) | p.Asp72Val |
| Coding change (HGVS c.) | c.215A>T |
| MANE Select transcript | [NM_000117](https://www.ncbi.nlm.nih.gov/nuccore/NM_000117) |
| dbSNP | [rs794729021](https://www.ncbi.nlm.nih.gov/snp/rs794729021/) |
| Variant type | single nucleotide variant |
| Location | chrX:154379969-154379969 (GRCh38) |
| ClinVar | [VCV201783](https://www.ncbi.nlm.nih.gov/clinvar/variation/201783/) |

**All HGVS expressions:** `LRG_745:g.10534A>T`, `LRG_745t1:c.215A>T`, `NC_000023.10:g.153608329A>T`, `NC_000023.11:g.154379969A>T`, `NG_008677.1:g.10534A>T`, `NM_000117.3:c.215A>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3479) — no call either way
- REVEL 0.732 (pathogenic-leaning)
- SaProt LLR -6.528 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- Conservation: phyloP 6.669, GERP 0.375, phastCons 1 — highly conserved
- CADD: **PHRED 21.3**. 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 1.05** across the covering region of the MANE Select transcript (154,379,485–154,381,194), spanning 1,709 bp. Chi-square p 0.47. 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 (A>G, Δ0.89 donor 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 (gnomAD v4.1): grpmax **0.000894%** (nfe) · FAF95 0.000384% · FAF99 0.000278% · 8/895,225 in the highest group · 9/1,097,912 alleles overall — very rare (popmax 0.000894%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00214% | 46,731 |
| European (non-Finnish) (grpmax) | 0.000894% | 111,903 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **72** lies in the 'interaction with f-actin' region.

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.Asp72Val falls in the interaction with f-actin region.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-11.

**Submitter consensus:** unanimous (6/6 Uncertain significance).

**Submission history:** 6 submissions (2015–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-15 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-04-30 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-17 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-11-02 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-12-06 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-06-11 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, not specified, Emery-Dreifuss muscular dystrophy, X-linked Emery-Dreifuss muscular dystrophy, AllHighlyPenetrant, none provided, Scapuloperoneal syndrome, X-linked (formerly), Humeroperoneal neuromuscular disease, (formerly), Muscular dystrophy, tardive Emery-Dreifuss type, with contractures.

## Similar variants {#similar}

Related EMD variant pages (same residue, condition, or type): [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), [EMD c.399+2T>C](/variant/emd-c-399-plus-2t-c), [EMD c.450-2A>G](/variant/emd-c-450-minus-2a-g).

### 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 201783). 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.*