# NM_002444.3(MSN):c.795G>A (p.Pro265=)

https://sugi.bio/variant/msn-p-pro265

## Summary

**MSN p.Pro265= (c.795G>A)** is classified **Uncertain significance** in MSN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-09). Very rare (popmax 0.000113%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.000113%, nfe)

## For patients & families {#patients}

This is a change in the MSN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [MSN](https://sugi.bio/atlas/gene/MSN/) |
| Protein change (HGVS p.) | p.Pro265= |
| Coding change (HGVS c.) | c.795G>A |
| MANE Select transcript | [NM_002444](https://www.ncbi.nlm.nih.gov/nuccore/NM_002444) |
| Variant type | single nucleotide variant |
| Location | chrX:65733280-65733280 (GRCh38) |
| ClinVar | [VCV4951160](https://www.ncbi.nlm.nih.gov/clinvar/variation/4951160/) |

**All HGVS expressions:** `NC_000023.10:g.64953142G>A`, `NC_000023.11:g.65733280G>A`, `NG_012516.1:g.70632G>A`, `NG_012516.2:g.149905G>A`, `NM_001440778.1:c.798G>A`, `NM_002444.3:c.795G>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 gain** (Δ 0.82) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.629, GERP -1.64, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 25.2**. 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 **0.35**, acceptor gain **0.00**, donor gain **0.82**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.35**, acceptor gain **0.00**, donor gain **0.82**.
- Pangolin: Δ**0.60** (loss), gain 0.40 / loss 0.60. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000113%** (nfe) · 1/882,018 in the highest group · 1/1,196,935 alleles overall — very rare (popmax 0.000113%, nfe).

*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}


Curated gene–disease validity (ClinGen):

- **combined immunodeficiency due to moesin deficiency** — Definitive (XL)

## Protein context {#protein}

Residue **265** lies in the ferm domain.

AlphaFold model confidence (whole protein): pLDDT 86.77, 62% of residues very-high.

**10 experimental structure(s)** (PDB): [1E5W](https://www.rcsb.org/structure/1E5W), [1EF1](https://www.rcsb.org/structure/1EF1), [1SGH](https://www.rcsb.org/structure/1SGH), [6TXQ](https://www.rcsb.org/structure/6TXQ), [6TXS](https://www.rcsb.org/structure/6TXS), [8CIR](https://www.rcsb.org/structure/8CIR) — incl. mutant structure 8CIT.

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

*Describes the biological roles of MSN (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:** MSN's established molecular role includes double-stranded RNA binding. p.Pro265= falls in the ferm domain. In Reactome, MSN is annotated in disease pathway(s) including **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** MSN loss or alteration is curated in [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370).

### Pathways affected {#pathways}

MSN participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation](https://reactome.org/content/detail/R-HSA-8950505) | curated |
| [Recycling pathway of L1](https://reactome.org/content/detail/R-HSA-437239) | electronic |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |

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

**Molecular function:** double-stranded RNA binding, signaling receptor binding, enzyme binding, protein kinase binding, cell adhesion molecule binding.

**Biological process:** immunological synapse formation, leukocyte cell-cell adhesion, regulation of cell shape, regulation of cell size, positive regulation of gene expression, gland morphogenesis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-09 |

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

## Similar variants {#similar}

Related MSN variant pages (same residue, condition, or type): [MSN p.Pro265Leu](/variant/msn-p-pro265leu), [MSN p.Arg171Trp](/variant/msn-p-arg171trp), [MSN p.Ala122Thr](/variant/msn-p-ala122thr), [MSN p.Arg273Trp](/variant/msn-p-arg273trp), [MSN p.Arg293Cys](/variant/msn-p-arg293cys), [MSN p.Arg294Cys](/variant/msn-p-arg294cys), [MSN p.Arg295His](/variant/msn-p-arg295his), [MSN p.Arg393His](/variant/msn-p-arg393his).

### 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 4951160). 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.*