# NM_020831.6(MRTFA):c.682C>T (p.Pro228Ser)

https://sugi.bio/variant/mrtfa-p-pro228ser

## Summary

**MRTFA p.Pro228Ser (c.682C>T)** is classified **Uncertain significance** in MRTFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-27). AlphaMissense: ambiguous (0.384); Very rare (popmax 0.00503%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1320763682 · 2 submitters · AlphaMissense ambiguous · very rare (popmax 0.00503%, amr)

## For patients & families {#patients}

This is a change in the MRTFA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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 | [MRTFA](https://sugi.bio/atlas/gene/MRTFA/) |
| Protein change (HGVS p.) | p.Pro228Ser |
| Coding change (HGVS c.) | c.682C>T |
| MANE Select transcript | [NM_020831](https://www.ncbi.nlm.nih.gov/nuccore/NM_020831) |
| dbSNP | [rs1320763682](https://www.ncbi.nlm.nih.gov/snp/rs1320763682/) |
| Variant type | single nucleotide variant |
| Location | chr22:40424301-40424301 (GRCh38) |
| ClinVar | [VCV1908657](https://www.ncbi.nlm.nih.gov/clinvar/variation/1908657/) |

**All HGVS expressions:** `LRG_1427:g.217419C>T`, `LRG_1427t1:c.682C>T`, `LRG_1427t2:c.487C>T`, `NC_000022.10:g.40820305G>A`, `NC_000022.11:g.40424301G>A`, `NG_065810.1:g.217419C>T`, `NM_001282660.2:c.382C>T`, `NM_001282661.3:c.682C>T`, `NM_001282662.3:c.682C>T`, `NM_001318139.2:c.487C>T`, `NM_020831.3:c.382C>T`, `NM_020831.6:c.682C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.384) — no call either way
- REVEL 0.576 (indeterminate)
- SaProt LLR -6.379 (tolerated)
- Conservation: phyloP 11.789, GERP 2.56, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P128S** vs ClinVar **P228S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 26.7**. 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 1.06** across the covering region of the MANE Select transcript (40,411,393–40,424,318), spanning 12,925 bp. Chi-square p 0.043. 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 (G>C, Δ0.22 acceptor 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 **0.00503%** (amr) · FAF95 0.00133% · FAF99 0.00067% · 3/59,694 in the highest group · 9/1,612,554 alleles overall — very rare (popmax 0.00503%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00503% | 19,898 |
| European (non-Finnish) | 0.000509% | 196,573 |

*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}

**MRTFA** population constraint: LOEUF 0.389, pLI 0.99999, missense-Z -0.061525. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **128** lies in the 'mediates interaction with scai and actb' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 56.59, 19% of residues very-high.

**2 experimental structure(s)** (PDB): [2KVU](https://www.rcsb.org/structure/2KVU), [2KW9](https://www.rcsb.org/structure/2KW9).

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

*Describes the biological roles of MRTFA (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:** MRTFA's established molecular role includes transcription coactivator activity. p.Pro228Ser falls in the mediates interaction with scai and actb region.


### Pathways affected {#pathways}

MRTFA participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [SUMOylation of transcription cofactors](https://reactome.org/content/detail/R-HSA-3899300) | curated |

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

**Molecular function:** transcription coactivator activity, actin binding, leucine zipper domain binding.

**Biological process:** wound healing, spreading of cells, positive regulation of transcription by RNA polymerase II, smooth muscle cell differentiation, positive regulation of miRNA transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-27.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-27 |

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

## Similar variants {#similar}

Related MRTFA variant pages (same residue, condition, or type): [MRTFA p.Ala352Thr](/variant/mrtfa-p-ala352thr), [MRTFA p.Ala360Thr](/variant/mrtfa-p-ala360thr), [MRTFA p.Ala429Ser](/variant/mrtfa-p-ala429ser), [MRTFA p.Ala479Gly](/variant/mrtfa-p-ala479gly), [MRTFA p.Ala479Val](/variant/mrtfa-p-ala479val), [MRTFA p.Ala534Thr](/variant/mrtfa-p-ala534thr), [MRTFA p.Ala537Val](/variant/mrtfa-p-ala537val), [MRTFA p.Ala616Val](/variant/mrtfa-p-ala616val).

### 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 1908657). 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.*