# NM_000268.4(NF2):c.1466C>T (p.Ala489Val)

https://sugi.bio/variant/nf2-p-ala489val

## Summary

**NF2 p.Ala489Val (c.1466C>T)** is classified **Uncertain significance** in NF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.0649); Absent from gnomAD v4.1; Associated with NF2-related schwannomatosis.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1156963577 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## 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 2 submitters, and is linked to NF2-related schwannomatosis.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 43 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NF2 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Full NF2-related schwannomatosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neuroma — Very frequent (99-80%)
- Sensorineural hearing impairment — Frequent (79-30%)
- Abnormality of the eye — Frequent (79-30%)
- Myelopathy — Frequent (79-30%)
- Meningioma — Frequent (79-30%)
- Reduced visual acuity — Frequent (79-30%)
- Posterior subcapsular cataract — Frequent (79-30%)
- Bilateral vestibular schwannoma — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007193/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.Ala489Val |
| Coding change (HGVS c.) | c.1466C>T |
| MANE Select transcript | [NM_000268](https://www.ncbi.nlm.nih.gov/nuccore/NM_000268) |
| dbSNP | [rs1156963577](https://www.ncbi.nlm.nih.gov/snp/rs1156963577/) |
| Variant type | single nucleotide variant |
| Location | chr22:29678215-29678215 (GRCh38) |
| ClinVar | [VCV1393924](https://www.ncbi.nlm.nih.gov/clinvar/variation/1393924/) |

**All HGVS expressions:** `LRG_511:g.79660C>T`, `LRG_511t1:c.1466C>T`, `LRG_511t2:c.1466C>T`, `NC_000022.10:g.30074204C>T`, `NC_000022.11:g.29678215C>T`, `NG_009057.1:g.79660C>T`, `NM_000268.4:c.1466C>T`, `NM_016418.5:c.1466C>T`, `NM_181825.3:c.1466C>T`, `NM_181828.3:c.1340C>T`, `NM_181829.3:c.1343C>T`, `NM_181830.3:c.1217C>T`, `NM_181831.3:c.1217C>T`, `NM_181832.3:c.1466C>T`, `NM_181833.3:c.448-16537C>T`, `NR_156186.2:n.1948C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0649)
- REVEL 0.238 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.057 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.675, GERP 2.03, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.2**. 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.*
- Regional missense constraint: **o/e 0.83** across the covering region of the MANE Select transcript (29,673,368–29,694,799), spanning 21,431 bp. Chi-square p 0.0072. 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 (C>G, Δ0.47 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: **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}

**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}


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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-15.

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

**Submission history:** 2 submissions (2021–2024); 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 | 2021-08-28 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-15 |

## Associated conditions {#conditions}

[NF2-related schwannomatosis](https://sugi.bio/atlas/disease/nf2-related-schwannomatosis/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Neurofibromatosis, type 2, Hereditary cancer-predisposing syndrome, BILATERAL ACOUSTIC NEUROFIBROMATOSIS, NF2-Related Schwannomatosis, SCHWANNOMATOSIS, VESTIBULAR, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome.

## Similar variants {#similar}

Related NF2 variant pages (same residue, condition, or type): [NF2 p.Ala489Glu](/variant/nf2-p-ala489glu), [NF2 p.Ala489del](/variant/nf2-p-ala489del), [NF2 c.115-1G>A](/variant/nf2-c-115-minus-1g-a), [NF2 c.1340+1G>T](/variant/nf2-c-1340-plus-1g-t), [NF2 c.1340+2T>G](/variant/nf2-c-1340-plus-2t-g), [NF2 c.1447-1G>A](/variant/nf2-c-1447-minus-1g-a), [NF2 c.1575-2A>G](/variant/nf2-c-1575-minus-2a-g), [NF2 c.1737+1G>T](/variant/nf2-c-1737-plus-1g-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 1393924). 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.*