Is NEFL p.Gln537Arg (c.1610A>G) pathogenic?

NEFL p.Gln537Arg (c.1610A>G) is classified Conflicting classifications of pathogenicity in NEFL (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-08-13). AlphaMissense: likely benign (0.0969); Ultra-rare (popmax 0.0994%, nfe); Associated with Charcot-Marie-Tooth disease type 1F.

What condition is associated with NEFL p.Gln537Arg (c.1610A>G)?

NEFL p.Gln537Arg (c.1610A>G) is associated with Charcot-Marie-Tooth disease type 1F, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease, dominant intermediate G (ClinVar).

How common is NEFL p.Gln537Arg (c.1610A>G) in the general population?

NEFL p.Gln537Arg (c.1610A>G) is ultra-rare (popmax 0.0994%, nfe) (gnomAD).

How is Charcot-Marie-Tooth disease type 1F inherited?

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

What do computational predictors say about NEFL p.Gln537Arg (c.1610A>G)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

NEFL p.Gln537Arg

c.1610A>G · rs377121179 · VCV220209

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0994%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Charcot-Marie-Tooth disease type 1F

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	21.0	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 0.0994% European (non-Finnish) · 1,172/1,179,638 alleles

Filtering AF 0.0945% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0927%

Overall 0.0826% 1,333/1,613,712 alleles · ultra-rare exomes 1,251/1,461,378 · genomes 82/152,334 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.154%	651
European (non-Finnish)grpmax	0.0994%	1,007
Admixed American	0.0816%	1,225
African / African-American	0.0147%	6,823
Finnishnot grpmax-eligible	0.00781%	12,801

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln537Arg
Coding: c.1610A>G
MANE Select: NM_006158
dbSNP: rs377121179
Type: single nucleotide variant
Location: chr8:24952832 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 537: the 'tail' region; the 'tail, subdomain b (acidic)' region; the 'disordered' region

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

Disease context

Charcot-Marie-Tooth disease type 1F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 2E Charcot-Marie-Tooth disease, dominant intermediate G

For Charcot-Marie-Tooth disease type 1F (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

NEFL p.Gln537= Likely benign ★★ same residue
NEFL p.Arg399Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Arg421Ter Pathogenic ★★ same condition
NEFL p.Asn98His 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

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-gln537arg (accessed [today's date]).

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