Is NAGLU p.Arg464Pro (c.1391G>C) pathogenic?

NAGLU p.Arg464Pro (c.1391G>C) is classified Uncertain significance in NAGLU (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.7472); Absent from gnomAD v4.1; Associated with mucopolysaccharidosis type 3B.

What condition is associated with NAGLU p.Arg464Pro (c.1391G>C)?

NAGLU p.Arg464Pro (c.1391G>C) is associated with mucopolysaccharidosis type 3B, Charcot-Marie-Tooth disease axonal type 2V (ClinVar).

How common is NAGLU p.Arg464Pro (c.1391G>C) in the general population?

NAGLU p.Arg464Pro (c.1391G>C) is absent from gnomAD v4.1 (gnomAD).

How is Mucopolysaccharidosis type 3 inherited?

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

What do computational predictors say about NAGLU p.Arg464Pro (c.1391G>C)?

AlphaMissense predicts likely pathogenic (score 0.7472) — an in-silico prediction, not a clinical call.

NAGLU p.Arg464Pro

c.1391G>C · rs377282648 · VCV2001140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7472 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 3B

Computational evidence

Protein change
AlphaMissense	0.7472	likely pathogenic
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -16.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,962 bp · p 0.0079 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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: NAGLU
Protein: p.Arg464Pro
Coding: c.1391G>C
MANE Select: NM_000263
dbSNP: rs377282648
Type: single nucleotide variant
Location: chr17:42543397 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 1 PDB
Residue 464: a UniProt-annotated variant site (in mps3b)

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

Disease context

mucopolysaccharidosis type 3B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2V

For Mucopolysaccharidosis type 3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Brazil)

Similar variants

NAGLU p.Arg464Ter Pathogenic ★★ same residue
NAGLU p.Arg464Gln 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

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-arg464pro (accessed [today's date]).

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