Is NEFL p.Ser49Phe (c.146C>T) pathogenic?

NEFL p.Ser49Phe (c.146C>T) is classified Uncertain significance in NEFL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-24). AlphaMissense: ambiguous (0.3485); Very rare (popmax 0.00133%, afr); Associated with Charcot-Marie-Tooth disease, dominant intermediate G.

What condition is associated with NEFL p.Ser49Phe (c.146C>T)?

NEFL p.Ser49Phe (c.146C>T) is associated with Charcot-Marie-Tooth disease, dominant intermediate G (ClinVar).

How common is NEFL p.Ser49Phe (c.146C>T) in the general population?

NEFL p.Ser49Phe (c.146C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NEFL p.Ser49Phe (c.146C>T)?

AlphaMissense predicts ambiguous (score 0.3485) — an in-silico prediction, not a clinical call.

NEFL p.Ser49Phe

c.146C>T · rs779764890 · VCV444743

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Charcot-Marie-Tooth disease, dominant intermediate G

Computational evidence

Protein change
AlphaMissense	0.3485	ambiguous
SaProt	LLR -13.28	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.92, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	32.0	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 0.00133% African / African-American · 1/74,924 alleles

Overall 0.000124% 2/1,607,220 alleles · very rare exomes 2/1,455,050 · genomes 0/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,924
South Asian	0.00111%	89,728

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.Ser49Phe
Coding: c.146C>T
MANE Select: NM_006158
dbSNP: rs779764890
Type: single nucleotide variant
Location: chr8:24956370 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 49: the 'head' region

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

Disease context

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

Similar variants

NEFL p.Ser49= Likely benign ★ same residue
NEFL p.Asn98His Likely pathogenic ★★ same condition
NEFL p.Asn98Ser Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Glu396Lys Pathogenic ★★ same condition
NEFL p.Glu140Lys Uncertain significance ★★ ⚠ same condition
NEFL p.Glu488Lys Uncertain significance ★★ ⚠ same condition
NEFL p.Leu94His Uncertain significance ★★ ⚠ same condition
NEFL p.Gln537Arg Conflicting classifications of pathogenicity ★ ⚠ 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-ser49phe (accessed [today's date]).

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