# NM_000268.4(NF2):c.1774T>C (p.Phe592Leu)

https://sugi.bio/variant/nf2-p-phe592leu

## Summary

**NF2 p.Phe592Leu (c.1774T>C)** is classified **Conflicting classifications of pathogenicity** in NF2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.9946); Ultra-rare (popmax 0.0198%, sas); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs764972504 · 10 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0198%, sas)

## For patients & families {#patients}

This is a change in the NF2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 10 submitters, 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.Phe592Leu |
| Coding change (HGVS c.) | c.1774T>C |
| MANE Select transcript | [NM_000268](https://www.ncbi.nlm.nih.gov/nuccore/NM_000268) |
| dbSNP | [rs764972504](https://www.ncbi.nlm.nih.gov/snp/rs764972504/) |
| Variant type | single nucleotide variant |
| Location | chr22:29694788-29694788 (GRCh38) |
| ClinVar | [VCV412213](https://www.ncbi.nlm.nih.gov/clinvar/variation/412213/) |

**All HGVS expressions:** `LRG_511:g.96233T>C`, `LRG_511t1:c.1774T>C`, `LRG_511t2:c.*46T>C`, `NC_000022.10:g.30090777T>C`, `NC_000022.11:g.29694788T>C`, `NG_009057.1:g.96233T>C`, `NM_000268.4:c.1774T>C`, `NM_016418.5:c.*46T>C`, `NM_181828.3:c.*46T>C`, `NM_181829.3:c.*46T>C`, `NM_181830.3:c.*46T>C`, `NM_181832.3:c.*61T>C`, `NM_181833.3:c.484T>C`, `NR_156186.2:n.2256T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9946)
- REVEL 0.687 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.407 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.907, GERP 1.85, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in NF2 (of 3,522 modeled).
- CADD: **PHRED 26.2**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0198%** (sas) · FAF95 0.0127% · FAF99 0.0106% · 18/90,932 in the highest group · 79/1,613,414 alleles overall — ultra-rare (popmax 0.0198%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0198% | 5,052 |
| Middle Eastern | 0.0164% | 6,084 |
| Remaining individuals (not grpmax-eligible) | 0.00961% | 10,408 |
| European (non-Finnish) | 0.00458% | 21,847 |

*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 **592** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (4 Likely benign, 4 Uncertain significance, 1 Benign, 1 Uncertain Significance).

**Submission history:** 10 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Center of Medical Genetics and Primary Health Care | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-04 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-11-07 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-06-16 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-03-01 |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2024-09-23 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Neurofibromatosis, type 2, not provided, Malignant tumor of breast, NF2-related disorder, NF2-related condition, Tumor predisposition, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary.

## Similar variants {#similar}

Related NF2 variant pages (same residue, condition, or type): [NF2 p.Phe592=](/variant/nf2-p-phe592), [NF2 p.Phe592del](/variant/nf2-p-phe592del), [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 412213). 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.*