Is NAGLU p.Pro216= (c.648C>G) pathogenic?

NAGLU p.Pro216= (c.648C>G) is classified Likely benign in NAGLU (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-24). Very rare (popmax 0.00833%, amr); Associated with Charcot-Marie-Tooth disease axonal type 2V.

What condition is associated with NAGLU p.Pro216= (c.648C>G)?

NAGLU p.Pro216= (c.648C>G) is associated with Charcot-Marie-Tooth disease axonal type 2V, mucopolysaccharidosis type 3B (ClinVar).

How common is NAGLU p.Pro216= (c.648C>G) in the general population?

NAGLU p.Pro216= (c.648C>G) is very rare (popmax 0.00833%, amr) (gnomAD).

NAGLU p.Pro216=

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.648C>G · rs755855749 · VCV1108929

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -4.5
Overall
CADD	1.005	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,010 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000805% 13/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,002
Remaining individualsnot grpmax-eligible	0.0032%	31,245
East Asian	0.00223%	44,896
African / African-American	0.00133%	74,926
European (non-Finnish)	0.000339%	295,011

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.Pro216=
Coding: c.648C>G
MANE Select: NM_000263
dbSNP: rs755855749
Type: single nucleotide variant
Location: chr17:42538455 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 1 PDB
Residue 216: an α-helix; 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.Pro216Arg Uncertain significance ★ ⚠ same residue
NAGLU p.Pro216His Uncertain significance ★ ⚠ same residue
NAGLU p.Pro216Ser 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

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-pro216 (accessed [today's date]).

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