# NM_002397.5(MEF2C):c.728del (p.Pro243fs)

https://sugi.bio/variant/mef2c-p-pro243fs

## Summary

**MEF2C p.Pro243fs (c.728del)** is classified **Pathogenic** in MEF2C (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-03). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1581392920 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MEF2C 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 | [MEF2C](https://sugi.bio/atlas/gene/MEF2C/) |
| Protein change (HGVS p.) | p.Pro243fs |
| Coding change (HGVS c.) | c.728del |
| MANE Select transcript | [NM_002397](https://www.ncbi.nlm.nih.gov/nuccore/NM_002397) |
| dbSNP | [rs1581392920](https://www.ncbi.nlm.nih.gov/snp/rs1581392920/) |
| Variant type | Deletion |
| Location | chr5:88731811-88731811 (GRCh38) |
| ClinVar | [VCV817755](https://www.ncbi.nlm.nih.gov/clinvar/variation/817755/) |

**All HGVS expressions:** `NC_000005.10:g.88731815del`, `NC_000005.9:g.88027632del`, `NG_023427.1:g.177295del`, `NM_001131005.2:c.722del`, `NM_001193347.1:c.782del`, `NM_001193348.1:c.584del`, `NM_001193349.3:c.584del`, `NM_001193350.2:c.728del`, `NM_001308002.3:c.728del`, `NM_001363581.2:c.728del`, `NM_001364329.2:c.728del`, `NM_001364330.2:c.728del`, `NM_001364331.2:c.728del`, `NM_001364332.2:c.584del`, `NM_001364333.2:c.728del`, `NM_001364334.2:c.728del`, `NM_001364335.2:c.728del`, `NM_001364336.2:c.728del`, `NM_001364337.2:c.728del`, `NM_001364338.2:c.782del`, `NM_001364339.2:c.728del`, `NM_001364340.2:c.728del`, `NM_001364341.2:c.728del`, `NM_001364342.2:c.728del`, `NM_001364343.2:c.722del`, `NM_001364344.2:c.584del`, `NM_001364345.2:c.728del`, `NM_001364346.2:c.728del`, `NM_001364347.2:c.728del`, `NM_001364348.2:c.728del`, `NM_001364349.2:c.728del`, `NM_001364350.2:c.728del`, `NM_001364352.2:c.722del`, `NM_001364353.2:c.350del`, `NM_001364354.2:c.584del`, `NM_001364355.2:c.584del`, `NM_001364356.2:c.350del`, `NM_001364357.2:c.302del`, `NM_002397.5:c.728del`

## 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 0.363, GERP -3.37, phastCons 0.971 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.212, 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 7 of 11**, 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}

**MEF2C** population constraint: LOEUF 0.212, pLI 1, missense-Z 4.8294; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 1/3. *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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 56.80, 20% of residues very-high.

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

*Describes the biological roles of MEF2C (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:** MEF2C's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding.


### Pathways affected {#pathways}

MEF2C participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | curated |
| [Cardiogenesis](https://reactome.org/content/detail/R-HSA-9733709) | electronic |
| [ERK/MAPK targets](https://reactome.org/content/detail/R-HSA-198753) | electronic |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | electronic |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | electronic |
| [MECP2 regulates transcription factors](https://reactome.org/content/detail/R-HSA-9022707) | electronic |
| [Transcriptional activation of mitochondrial biogenesis](https://reactome.org/content/detail/R-HSA-2151201) | electronic |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA binding, minor groove of adenine-thymine-rich DNA binding, DNA-binding transcription factor activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, MAPK cascade, regulation of DNA-templated transcription, heart development, positive regulation of gene expression, myotube differentiation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-08-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2018-08-03 |

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

## Similar variants {#similar}

Related MEF2C variant pages (same residue, condition, or type): [MEF2C p.Pro243=](/variant/mef2c-p-pro243), [MEF2C p.Pro243Gln](/variant/mef2c-p-pro243gln), [MEF2C p.Leu277_Leu278insTer](/variant/mef2c-p-leu277-leu278inster), [MEF2C c.638-9del](/variant/mef2c-c-638-minus-9del), [MEF2C c.965-6_965-2del](/variant/mef2c-c-965-minus-6-965-minus-2del), [MEF2C c.402+184del](/variant/mef2c-c-402-plus-184del), [MEF2C c.54+1del](/variant/mef2c-c-54-plus-1del), [MEF2C c.811_814delTCTG](/variant/mef2c-c-811-814deltctg).

### 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 817755). 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.*