# NM_020831.6(MRTFA):c.306G>A (p.Pro102=)

https://sugi.bio/variant/mrtfa-p-pro102

## Summary

**MRTFA p.Pro102= (c.306G>A)** is classified **Uncertain significance** in MRTFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-02). Ultra-rare (popmax 0.033%, mid).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs868096885 · 2 submitters · ultra-rare (popmax 0.033%, mid)

## 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.Pro102= |
| Coding change (HGVS c.) | c.306G>A |
| MANE Select transcript | [NM_020831](https://www.ncbi.nlm.nih.gov/nuccore/NM_020831) |
| dbSNP | [rs868096885](https://www.ncbi.nlm.nih.gov/snp/rs868096885/) |
| Variant type | single nucleotide variant |
| Location | chr22:40463222-40463222 (GRCh38) |
| ClinVar | [VCV2971755](https://www.ncbi.nlm.nih.gov/clinvar/variation/2971755/) |

**All HGVS expressions:** `LRG_1427:g.178498G>A`, `LRG_1427t1:c.306G>A`, `LRG_1427t2:c.111G>A`, `NC_000022.10:g.40859226C>T`, `NC_000022.11:g.40463222C>T`, `NG_065810.1:g.178498G>A`, `NM_001282660.2:c.6G>A`, `NM_001282661.3:c.306G>A`, `NM_001282662.3:c.306G>A`, `NM_001318139.2:c.111G>A`, `NM_020831.6:c.306G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -1.324, GERP -5.33 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.08**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.01**.
- Population frequency (gnomAD v4.1): grpmax **0.033%** (mid) · FAF95 0.00582% · FAF99 0.00242% · 2/6,056 in the highest group · 35/1,613,790 alleles overall — ultra-rare (popmax 0.033%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.033% | 3,028 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,246 |
| European (non-Finnish) | 0.00254% | 39,325 |
| East Asian | 0.00223% | 44,884 |

*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 **102** lies in the 'mediates interaction with scai and actb' 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.Pro102= 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 2024-05-02.

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

**Submission history:** 2 submissions (2019–2024); 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 | 2024-05-02 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-06-27 |

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

## Similar variants {#similar}

Related MRTFA variant pages (same residue, condition, or type): [MAL p.Ala102Thr](/variant/mal-p-ala102thr), [MRTFA p.Pro102Leu](/variant/mrtfa-p-pro102leu), [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).

### 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 2971755). 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.*