# NM_002397.5(MEF2C):c.44G>C (p.Arg15Pro)

https://sugi.bio/variant/mef2c-p-arg15pro

## Summary

**MEF2C p.Arg15Pro (c.44G>C)** is classified **Pathogenic** in MEF2C (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-12). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1202957297 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MEF2C gene that is considered disease-causing, submitted by 4 submitters, and is linked to neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language.

*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/0024910/index) · [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.Arg15Pro |
| Coding change (HGVS c.) | c.44G>C |
| MANE Select transcript | [NM_002397](https://www.ncbi.nlm.nih.gov/nuccore/NM_002397) |
| dbSNP | [rs1202957297](https://www.ncbi.nlm.nih.gov/snp/rs1202957297/) |
| Variant type | single nucleotide variant |
| Location | chr5:88823745-88823745 (GRCh38) |
| ClinVar | [VCV1685944](https://www.ncbi.nlm.nih.gov/clinvar/variation/1685944/) |

**All HGVS expressions:** `NC_000005.10:g.88823745C>G`, `NC_000005.9:g.88119562C>G`, `NG_023427.1:g.85361G>C`, `NM_001131005.2:c.44G>C`, `NM_001193347.1:c.44G>C`, `NM_001193348.1:c.44G>C`, `NM_001193349.3:c.44G>C`, `NM_001193350.2:c.44G>C`, `NM_001308002.3:c.44G>C`, `NM_001363581.2:c.44G>C`, `NM_001364329.2:c.44G>C`, `NM_001364330.2:c.44G>C`, `NM_001364331.2:c.44G>C`, `NM_001364332.2:c.44G>C`, `NM_001364333.2:c.44G>C`, `NM_001364334.2:c.44G>C`, `NM_001364335.2:c.44G>C`, `NM_001364336.2:c.44G>C`, `NM_001364337.2:c.44G>C`, `NM_001364338.2:c.44G>C`, `NM_001364339.2:c.44G>C`, `NM_001364340.2:c.44G>C`, `NM_001364341.2:c.44G>C`, `NM_001364342.2:c.44G>C`, `NM_001364343.2:c.44G>C`, `NM_001364344.2:c.44G>C`, `NM_001364345.2:c.44G>C`, `NM_001364346.2:c.44G>C`, `NM_001364347.2:c.44G>C`, `NM_001364348.2:c.44G>C`, `NM_001364349.2:c.44G>C`, `NM_001364350.2:c.44G>C`, `NM_001364352.2:c.44G>C`, `NM_001364354.2:c.44G>C`, `NM_001364355.2:c.44G>C`, `NM_002397.3:c.44G>C`, `NM_002397.4:c.44G>C`, `NM_002397.5:c.44G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9995) — concordant with the pathogenic call
- REVEL 0.876 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.01 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.72, GERP 2.26, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in MEF2C (of 2,775 modeled).
- CADD: **PHRED 33.0**. 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: **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: **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 **15** lies in the mads-box domain.

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.Arg15Pro falls in the mads-box domain.


### 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-12.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-11 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-05 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-12 |

## Associated conditions {#conditions}

[neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language](https://sugi.bio/atlas/disease/neurodevelopmental-disorder-with-hypotonia-stereotypic-hand-movements-and-impaired-language/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, not provided, none provided, Intellectual disability, autosomal dominant 20.

## Same-residue context {#hotspot}

Residue **15** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MEF2C p.Arg15Cys](/variant/mef2c-p-arg15cys), [MEF2C p.Arg15His](/variant/mef2c-p-arg15his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MEF2C variant pages (same residue, condition, or type): [MEF2C p.Arg15Cys](/variant/mef2c-p-arg15cys), [MEF2C p.Arg15His](/variant/mef2c-p-arg15his), [MEF2C p.Arg15Gly](/variant/mef2c-p-arg15gly), [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.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 2026-10-14); 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 1685944). 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.*