Is NEFL p.Pro22Ser (c.64C>T) pathogenic?

NEFL p.Pro22Ser (c.64C>T) is classified Pathogenic/Likely pathogenic in NEFL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2022-12-20). AlphaMissense: likely benign (0.1492); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with NEFL p.Pro22Ser (c.64C>T)?

NEFL p.Pro22Ser (c.64C>T) is associated with Inborn genetic diseases, peripheral neuropathy, Charcot-Marie-Tooth disease type 1C (ClinVar).

How common is NEFL p.Pro22Ser (c.64C>T) in the general population?

NEFL p.Pro22Ser (c.64C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NEFL p.Pro22Ser (c.64C>T)?

AlphaMissense predicts likely benign (score 0.1492) — an in-silico prediction, not a clinical call.

NEFL p.Pro22Ser

c.64C>T · rs28928910 · VCV14029

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1492 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1492	likely benign ⚠ discordant with ClinVar
SaProt	LLR -10.26	damaging
⇒ SaProt calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	23.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NEFL
Protein: p.Pro22Ser
Coding: c.64C>T
MANE Select: NM_006158
dbSNP: rs28928910
Type: single nucleotide variant
Location: chr8:24956452 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 22: the 'head' region; a UniProt-annotated variant site (in cmt2e)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

NEFL p.Pro22= Conflicting classifications of pathogenicity ★ same residue
NEFL p.Pro22Ala Uncertain significance ★ ⚠ same residue
NEFL p.Pro22His Conflicting classifications of pathogenicity ★ same residue
NEFL p.Pro22Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro22ser (accessed [today's date]).

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