Is NEFL p.Val76Ala (c.227T>C) pathogenic?

NEFL p.Val76Ala (c.227T>C) is classified Conflicting classifications of pathogenicity in NEFL (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-23). AlphaMissense: ambiguous (0.3525); Rare (popmax 0.829%, eas); Associated with Charcot-Marie-Tooth disease.

What condition is associated with NEFL p.Val76Ala (c.227T>C)?

NEFL p.Val76Ala (c.227T>C) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease type 1F (ClinVar).

How common is NEFL p.Val76Ala (c.227T>C) in the general population?

NEFL p.Val76Ala (c.227T>C) is rare (popmax 0.829%, eas) (gnomAD).

What do computational predictors say about NEFL p.Val76Ala (c.227T>C)?

AlphaMissense predicts ambiguous (score 0.3525) — an in-silico prediction, not a clinical call.

NEFL p.Val76Ala

c.227T>C · rs58907919 · VCV66686

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3525 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.829%, eas)

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.3525	ambiguous
SaProt	LLR -4.86	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP -0.94, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.829% East Asian · 371/44,764 alleles

Filtering AF 0.759% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.732%

Overall 0.0261% 420/1,611,162 alleles · rare exomes 381/1,458,930 · genomes 39/152,232 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.829%	121
South Asian	0.0388%	2,580
Remaining individualsnot grpmax-eligible	0.016%	6,240
Admixed American	0.00168%	59,682
European (non-Finnish)	0.000254%	392,958

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.Val76Ala
Coding: c.227T>C
MANE Select: NM_006158
dbSNP: rs58907919
Type: single nucleotide variant
Location: chr8:24956289 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 76: the 'head' region

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

Disease context

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

Also linked: Charcot-Marie-Tooth disease type 2E Charcot-Marie-Tooth disease type 1F

Similar variants

NEFL p.Val76= Likely benign ★ 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-val76ala (accessed [today's date]).

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