# NM_000268.4(NF2):c.1770del (p.Phe591fs)

https://sugi.bio/variant/nf2-p-phe591fs

## Summary

**NF2 p.Phe591fs (c.1770del)** is classified **Uncertain significance** in NF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the NF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NF2](https://sugi.bio/atlas/gene/NF2/) |
| Protein change (HGVS p.) | p.Phe591fs |
| Coding change (HGVS c.) | c.1770del |
| MANE Select transcript | [NM_000268](https://www.ncbi.nlm.nih.gov/nuccore/NM_000268) |
| Variant type | Deletion |
| Location | chr22:29694783-29694783 (GRCh38) |
| ClinVar | [VCV4661468](https://www.ncbi.nlm.nih.gov/clinvar/variation/4661468/) |

**All HGVS expressions:** `LRG_511:g.96229del`, `LRG_511t1:c.1770del`, `LRG_511t2:c.*42del`, `NC_000022.10:g.30090773del`, `NC_000022.11:g.29694784del`, `NG_009057.1:g.96229del`, `NM_000268.4:c.1770del`, `NM_001407053.1:c.1656del`, `NM_001407054.1:c.1647del`, `NM_001407055.1:c.1644del`, `NM_001407056.1:c.*42del`, `NM_001407057.1:c.1635del`, `NM_001407058.1:c.*57del`, `NM_001407059.1:c.*42del`, `NM_001407060.1:c.1607del`, `NM_001407062.1:c.1512del`, `NM_001407063.1:c.*57del`, `NM_001407064.1:c.1358del`, `NM_001407065.1:c.*42del`, `NM_001407067.1:c.*42del`, `NM_016418.5:c.*42del`, `NM_181828.3:c.*42del`, `NM_181829.3:c.*42del`, `NM_181830.3:c.*42del`, `NM_181832.3:c.*57del`, `NM_181833.3:c.480del`, `NR_176267.1:n.1155del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 11.859, GERP 0.788, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.187, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (16 of 16)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**NF2** population constraint: LOEUF 0.187, pLI 1, missense-Z 2.853; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **NF2-related schwannomatosis** — Definitive (AD)

## Protein context {#protein}

Residue **591** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.85, 67% of residues very-high.

**6 experimental structure(s)** (PDB): [1H4R](https://www.rcsb.org/structure/1H4R), [3U8Z](https://www.rcsb.org/structure/3U8Z), [4ZRI](https://www.rcsb.org/structure/4ZRI), [4ZRJ](https://www.rcsb.org/structure/4ZRJ), [6CDS](https://www.rcsb.org/structure/6CDS), [7LWH](https://www.rcsb.org/structure/7LWH).

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

*Describes the biological roles of NF2 (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:** NF2's established molecular role includes signaling adaptor activity.


### Pathways affected {#pathways}

NF2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHO GTPases activate PAKs](https://reactome.org/content/detail/R-HSA-5627123) | curated |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | curated |

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

**Molecular function:** signaling adaptor activity.

**Biological process:** negative regulation of cell population proliferation, Schwann cell proliferation, negative regulation of cell-cell adhesion, actin cytoskeleton organization, hippo signaling, regulation of hippo signaling.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-10 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome.

## Similar variants {#similar}

Related NF2 variant pages (same residue, condition, or type): [NF2 p.Phe591Val](/variant/nf2-p-phe591val), [NF2 c.1447-147_1447-8del](/variant/nf2-c-1447-minus-147-1447-minus-8del), [NF2 p.Leu551fs](/variant/nf2-p-leu551fs), [NF2 p.Met1_Ala4del](/variant/nf2-p-met1-ala4del), [NF2 c.810+23_810+25del](/variant/nf2-c-810-plus-23-810-plus-25del), [NF2 p.Asp503fs](/variant/nf2-p-asp503fs), [NF2 p.Asp513_Met514insTer](/variant/nf2-p-asp513-met514inster), [NF2 p.Gln165fs](/variant/nf2-p-gln165fs).

### 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 4661468). 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.*