# NM_001042492.3(NF1):c.2880T>C (p.Phe960=)

https://sugi.bio/variant/nf1-p-phe960

## Summary

**NF1 p.Phe960= (c.2880T>C)** is classified **Conflicting classifications of pathogenicity** in NF1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-05-18). Very rare (popmax 0.00017%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1377177645 · 5 submitters · 3 linked conditions · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the NF1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to Cardiovascular phenotype.

*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 | [NF1](https://sugi.bio/atlas/gene/NF1/) |
| Protein change (HGVS p.) | p.Phe960= |
| Coding change (HGVS c.) | c.2880T>C |
| MANE Select transcript | [NM_001042492](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042492) |
| dbSNP | [rs1377177645](https://www.ncbi.nlm.nih.gov/snp/rs1377177645/) |
| Variant type | single nucleotide variant |
| Location | chr17:31229864-31229864 (GRCh38) |
| ClinVar | [VCV762212](https://www.ncbi.nlm.nih.gov/clinvar/variation/762212/) |

**All HGVS expressions:** `LRG_214:g.139888T>C`, `LRG_214t1:c.2880T>C`, `LRG_214t2:c.2880T>C`, `NC_000017.10:g.29556882T>C`, `NC_000017.11:g.31229864T>C`, `NG_009018.1:g.139888T>C`, `NM_000267.4:c.2880T>C`, `NM_001042492.3:c.2880T>C`

## 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 **acceptor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.805, GERP 2.12, phastCons 1 — weakly conserved position
- CADD: **PHRED 7.147**. 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 **0.20**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,732 in the highest group · 2/1,611,738 alleles overall — very rare (popmax 0.00017%, 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}

**NF1** population constraint: LOEUF 0.449, pLI 0.99946, missense-Z 8.4243; 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):

- **neurofibromatosis type 1** — Definitive (AD)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}

Residue **960** lies in an α-helix.

**26 experimental structure(s)** (PDB): [1NF1](https://www.rcsb.org/structure/1NF1), [2D4Q](https://www.rcsb.org/structure/2D4Q), [2E2X](https://www.rcsb.org/structure/2E2X), [3P7Z](https://www.rcsb.org/structure/3P7Z), [3PEG](https://www.rcsb.org/structure/3PEG), [3PG7](https://www.rcsb.org/structure/3PG7) — incl. mutant structure 3PG7.

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

*Describes the biological roles of NF1 (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:** NF1's established molecular role includes GTPase activator activity. In Reactome, NF1 is annotated in disease pathway(s) including **RAS signaling downstream of NF1 loss-of-function variants**.

**Disease mechanism (Reactome):** NF1 loss or alteration is curated in [RAS signaling downstream of NF1 loss-of-function variants](https://reactome.org/content/detail/R-HSA-6802953).

### Pathways affected {#pathways}

NF1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [RAS signaling downstream of NF1 loss-of-function variants](https://reactome.org/content/detail/R-HSA-6802953) | curated |
| [Regulation of RAS by GAPs](https://reactome.org/content/detail/R-HSA-5658442) | curated |

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

**Molecular function:** GTPase activator activity, phosphatidylethanolamine binding, phosphatidylcholine binding.

**Biological process:** negative regulation of endothelial cell proliferation, negative regulation of cell migration, negative regulation of MAPK cascade, regulation of blood vessel endothelial cell migration, positive regulation of GTPase activity, regulation of angiogenesis.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-05-18.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance, 1 Benign).

**Submission history:** 5 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2022-03-15 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-12-24 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2026-05-18 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [neurofibromatosis type 1](https://sugi.bio/atlas/disease/neurofibromatosis-type-1/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Neurofibromatosis, type 1, Hereditary cancer-predisposing syndrome, not provided, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, NEUROFIBROMATOSIS, TYPE I, SOMATIC, Peripheral type neurofibromatosis.

## Same-residue context {#hotspot}

Residue **960** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NF1 p.Phe960fs](/variant/nf1-p-phe960fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NF1 variant pages (same residue, condition, or type): [NF1 p.Phe960Val](/variant/nf1-p-phe960val), [NF1 p.Phe960fs](/variant/nf1-p-phe960fs), [NF1 c.1062+1G>A](/variant/nf1-c-1062-plus-1g-a), [NF1 c.1062+1G>C](/variant/nf1-c-1062-plus-1g-c), [NF1 c.1062+2T>A](/variant/nf1-c-1062-plus-2t-a), [NF1 c.1062+2T>C](/variant/nf1-c-1062-plus-2t-c), [NF1 c.1062+3A>G](/variant/nf1-c-1062-plus-3a-g), [NF1 c.1062+3A>T](/variant/nf1-c-1062-plus-3a-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 762212). 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.*