Is NEFL p.Arg421Gln (c.1262G>A) pathogenic?

NEFL p.Arg421Gln (c.1262G>A) is classified Uncertain significance in NEFL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-08). AlphaMissense: likely benign (0.1725); Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Arg421Gln (c.1262G>A)?

NEFL p.Arg421Gln (c.1262G>A) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Arg421Gln (c.1262G>A) in the general population?

NEFL p.Arg421Gln (c.1262G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about NEFL p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely benign (score 0.1725) — an in-silico prediction, not a clinical call.

NEFL p.Arg421Gln

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.1262G>A · rs1463847045 · VCV2506825

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
AlphaMissense	0.1725	likely benign
SaProt	LLR -8.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,874 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,613,864 alleles · very rare exomes 23/1,461,710 · genomes 1/152,154 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
European (non-Finnish)	0.00195%	51,300

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.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_006158
dbSNP: rs1463847045
Type: single nucleotide variant
Location: chr8:24953703 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 421: the 'tail' region; the 'tail, subdomain a' 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.Arg421Ter Pathogenic ★★ same residue
NEFL p.Arg421= Likely benign ★ same residue
NEFL p.Arg399Ter Pathogenic/Likely 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-arg421gln (accessed [today's date]).

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