Is NEFL p.Pro252= (c.756C>T) pathogenic?

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.

What condition is associated with NEFL p.Pro252= (c.756C>T)?

NEFL p.Pro252= (c.756C>T) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Pro252= (c.756C>T) in the general population?

NEFL p.Pro252= (c.756C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

NEFL p.Pro252=

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2E inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.756C>T · VCV3713331

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.97, phastCons 1
Overall
CADD	14.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,066 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000992% 16/1,613,412 alleles · ultra-rare exomes 14/1,461,122 · genomes 2/152,290 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,107
Remaining individualsnot grpmax-eligible	0.0048%	20,826
East Asian	0.00446%	22,421
European (non-Finnish)	8.48e-05%	1,179,844

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NEFL
Protein: p.Pro252=
Coding: c.756C>T
MANE Select: NM_006158
Type: single nucleotide variant
Location: chr8:24955760 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 252: the if rod domain; the 'linker 12' region

Full NEFL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2E (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

NEFL p.Pro252Leu Uncertain significance ★★ ⚠ same residue
NEFL p.Arg399Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Arg421Ter Pathogenic ★★ same condition
NEFL p.Asn98Ser Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Glu186Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Glu396Lys Pathogenic ★★ same condition
NEFL p.Glu90Lys Pathogenic ★★ same condition
NEFL p.Pro22Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nefl-p-pro252 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown