Is NAGLU p.Phe245= (c.735C>T) pathogenic?

NAGLU p.Phe245= (c.735C>T) is classified Likely benign in NAGLU (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease axonal type 2V.

What condition is associated with NAGLU p.Phe245= (c.735C>T)?

NAGLU p.Phe245= (c.735C>T) is associated with Charcot-Marie-Tooth disease axonal type 2V, mucopolysaccharidosis type 3B (ClinVar).

How common is NAGLU p.Phe245= (c.735C>T) in the general population?

NAGLU p.Phe245= (c.735C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

NAGLU p.Phe245=

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2V inherited?

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

c.735C>T · rs539646032 · VCV1129196

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Charcot-Marie-Tooth disease axonal type 2V

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.316	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -4.5
Overall
CADD	2.304	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.00062% 10/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,253
East Asiangrpmax	0.00223%	44,892
South Asian	0.0022%	45,543
European (non-Finnish)	0.000424%	236,008

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: NAGLU
Protein: p.Phe245=
Coding: c.735C>T
MANE Select: NM_000263
dbSNP: rs539646032
Type: single nucleotide variant
Location: chr17:42538726 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 1 PDB
Residue 245: a UniProt-annotated variant site (in mps3b)

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

Disease context

Charcot-Marie-Tooth disease axonal type 2V — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mucopolysaccharidosis type 3B

For Autosomal dominant Charcot-Marie-Tooth disease type 2V (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Elderly

Similar variants

NAGLU p.Phe245Leu Uncertain significance ★ ⚠ same residue
NAGLU c.1021+1G>A Likely pathogenic ★★ same condition
NAGLU c.1022-2A>G Pathogenic/Likely pathogenic ★★ same condition
NAGLU c.383+1G>T Pathogenic/Likely pathogenic ★★ same condition
NAGLU c.384-1G>A Pathogenic ★★ same condition
NAGLU c.531+1G>A Pathogenic ★★ same condition
NAGLU c.531+1G>C Pathogenic ★★ same condition
NAGLU c.678+1G>A 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/naglu-p-phe245 (accessed [today's date]).

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