# NM_006158.5(NEFL):c.756C>T (p.Pro252=)

https://sugi.bio/variant/nefl-p-pro252

## Summary

**NEFL p.Pro252= (c.756C>T)** is classified **Likely benign** in NEFL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). Ultra-rare (popmax 0.011%, sas); Associated with Charcot-Marie-Tooth disease type 2E.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · ultra-rare (popmax 0.011%, sas)

## For patients & families {#patients}

This is a change in the NEFL gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease type 2E.

*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) | Adolescent, Adult, Childhood, Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NEFL is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Autosomal dominant Charcot-Marie-Tooth disease type 2E** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Gait disturbance — Very frequent (99-80%)
- Abnormal foot morphology — Very frequent (99-80%)
- Peripheral axonal neuropathy — Very frequent (99-80%)
- Upper limb muscle weakness — Very frequent (99-80%)
- Sensorimotor neuropathy — Very frequent (99-80%)
- Demyelinating motor neuropathy — Very frequent (99-80%)
- Lower limb muscle weakness — Very frequent (99-80%)
- Demyelinating sensory neuropathy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009193/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NEFL](https://sugi.bio/atlas/gene/NEFL/) |
| Protein change (HGVS p.) | p.Pro252= |
| Coding change (HGVS c.) | c.756C>T |
| MANE Select transcript | [NM_006158](https://www.ncbi.nlm.nih.gov/nuccore/NM_006158) |
| Variant type | single nucleotide variant |
| Location | chr8:24955760-24955760 (GRCh38) |
| ClinVar | [VCV3713331](https://www.ncbi.nlm.nih.gov/clinvar/variation/3713331/) |

**All HGVS expressions:** `LRG_259:g.5858C>T`, `LRG_259t1:c.756C>T`, `NC_000008.10:g.24813274G>A`, `NC_000008.11:g.24955760G>A`, `NG_008492.1:g.5858C>T`, `NM_006158.5:c.756C>T`

## 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 1.918, GERP 0.969, phastCons 1 — weakly conserved position
- CADD: **PHRED 14.34**. 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: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.011%** (sas) · FAF95 0.00594% · FAF99 0.00453% · 10/91,066 in the highest group · 16/1,613,412 alleles overall — ultra-rare (popmax 0.011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.011% | 9,107 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,826 |
| East Asian | 0.00446% | 22,421 |
| European (non-Finnish) | 8.48e-05% | 1,179,844 |

*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}

**NEFL** population constraint: LOEUF 0.986, pLI 8.8766e-10, missense-Z 0.64608; ClinGen dosage — haploinsufficiency 0/3, 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):

- **Charcot-Marie-Tooth disease type 2** — Definitive (AR)
- **Charcot-Marie-Tooth disease** — Definitive (AD)

## Protein context {#protein}

Residue **252** lies in the if rod domain; the 'linker 12' region.

AlphaFold model confidence (whole protein): pLDDT 73.66, 45% of residues very-high.

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

*Describes the biological roles of NEFL (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:** NEFL's established molecular role includes structural constituent of cytoskeleton. p.Pro252= falls in the if rod domain.


### Pathways affected {#pathways}

NEFL participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [Negative regulation of NMDA receptor-mediated neuronal transmission](https://reactome.org/content/detail/R-HSA-9617324) | electronic |
| [Ras activation upon Ca2+ influx through NMDA receptor](https://reactome.org/content/detail/R-HSA-442982) | electronic |
| [Unblocking of NMDA receptors, glutamate binding and activation](https://reactome.org/content/detail/R-HSA-438066) | electronic |

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

**Molecular function:** structural constituent of cytoskeleton, tubulin binding, identical protein binding.

**Biological process:** anterograde axonal transport, retrograde axonal transport, axonal transport of mitochondrion, neurofilament bundle assembly, intermediate filament organization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-04 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 2E](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-2e/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 2E, CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2E, CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2E.

## Similar variants {#similar}

Related NEFL variant pages (same residue, condition, or type): [NEFL p.Pro252Leu](/variant/nefl-p-pro252leu), [NEFL p.Arg399Ter](/variant/nefl-p-arg399ter), [NEFL p.Arg421Ter](/variant/nefl-p-arg421ter), [NEFL p.Asn98Ser](/variant/nefl-p-asn98ser), [NEFL p.Glu186Ter](/variant/nefl-p-glu186ter), [NEFL p.Glu396Lys](/variant/nefl-p-glu396lys), [NEFL p.Glu90Lys](/variant/nefl-p-glu90lys), [NEFL p.Pro22Ser](/variant/nefl-p-pro22ser).

### 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 3713331). 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.*