# NM_002397.5(MEF2C):c.236G>C (p.Arg79Pro)

https://sugi.bio/variant/mef2c-p-arg79pro

## Summary

**MEF2C p.Arg79Pro (c.236G>C)** is classified **Likely pathogenic** in MEF2C (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-09). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1554139693 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MEF2C gene that is considered likely disease-causing, 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.Arg79Pro |
| Coding change (HGVS c.) | c.236G>C |
| MANE Select transcript | [NM_002397](https://www.ncbi.nlm.nih.gov/nuccore/NM_002397) |
| dbSNP | [rs1554139693](https://www.ncbi.nlm.nih.gov/snp/rs1554139693/) |
| Variant type | single nucleotide variant |
| Location | chr5:88804620-88804620 (GRCh38) |
| ClinVar | [VCV546222](https://www.ncbi.nlm.nih.gov/clinvar/variation/546222/) |

**All HGVS expressions:** `NC_000005.10:g.88804620C>G`, `NC_000005.9:g.88100437C>G`, `NG_023427.1:g.104486G>C`, `NM_001131005.2:c.236G>C`, `NM_001193347.1:c.236G>C`, `NM_001193348.1:c.236G>C`, `NM_001193349.3:c.236G>C`, `NM_001193350.2:c.236G>C`, `NM_001308002.3:c.236G>C`, `NM_001363581.2:c.236G>C`, `NM_001364329.2:c.236G>C`, `NM_001364330.2:c.236G>C`, `NM_001364331.2:c.236G>C`, `NM_001364332.2:c.236G>C`, `NM_001364333.2:c.236G>C`, `NM_001364334.2:c.236G>C`, `NM_001364335.2:c.236G>C`, `NM_001364336.2:c.236G>C`, `NM_001364337.2:c.236G>C`, `NM_001364338.2:c.236G>C`, `NM_001364339.2:c.236G>C`, `NM_001364340.2:c.236G>C`, `NM_001364341.2:c.236G>C`, `NM_001364342.2:c.236G>C`, `NM_001364343.2:c.236G>C`, `NM_001364344.2:c.236G>C`, `NM_001364345.2:c.236G>C`, `NM_001364346.2:c.236G>C`, `NM_001364347.2:c.236G>C`, `NM_001364348.2:c.236G>C`, `NM_001364349.2:c.236G>C`, `NM_001364350.2:c.236G>C`, `NM_001364352.2:c.236G>C`, `NM_001364354.2:c.236G>C`, `NM_001364355.2:c.236G>C`, `NM_002397.5:c.236G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9999) — concordant with the pathogenic call
- REVEL 0.806 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.22 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.728, GERP 2.42, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in MEF2C (of 2,775 modeled).
- CADD: **PHRED 34.0**. 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 0.15** across the covering region of the MANE Select transcript (88,761,269–88,823,788), spanning 62,519 bp — the region is depleted of missense variation. Chi-square p 1.7e-23. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MEF2C (740 scored positions, the nearest 20 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

Residue **79** lies in a DNA-binding region.

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. p.Arg79Pro falls in a DNA-binding region.


### 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-05-09.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-05-09 |

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

## Similar variants {#similar}

Related MEF2C variant pages (same residue, condition, or type): [MEF2C p.Arg79=](/variant/mef2c-p-arg79), [MEF2C c.403-1G>T](/variant/mef2c-c-403-minus-1g-t), [MEF2C c.638-1G>A](/variant/mef2c-c-638-minus-1g-a), [MEF2C c.638-2A>C](/variant/mef2c-c-638-minus-2a-c), [MEF2C c.638-2A>G](/variant/mef2c-c-638-minus-2a-g), [MEF2C c.965-2A>G](/variant/mef2c-c-965-minus-2a-g), [MEF2C c.-26C>T](/variant/mef2c-c-minus-26c-t), [MEF2C c.-8C>T](/variant/mef2c-c-minus-8c-t).

### 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 546222). 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.*