Is NAGLU p.Arg149Pro (c.446G>C) pathogenic?

NAGLU p.Arg149Pro (c.446G>C) is classified Uncertain significance in NAGLU (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-25). AlphaMissense: ambiguous (0.5403); Very rare (popmax 8.47e-05%, nfe); Associated with mucopolysaccharidosis type 3B.

What condition is associated with NAGLU p.Arg149Pro (c.446G>C)?

NAGLU p.Arg149Pro (c.446G>C) is associated with mucopolysaccharidosis type 3B, Charcot-Marie-Tooth disease axonal type 2V (ClinVar).

How common is NAGLU p.Arg149Pro (c.446G>C) in the general population?

NAGLU p.Arg149Pro (c.446G>C) is very rare (popmax 8.47e-05%, nfe) (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.Arg149Pro (c.446G>C)?

AlphaMissense predicts ambiguous (score 0.5403) — an in-silico prediction, not a clinical call.

NAGLU p.Arg149Pro

c.446G>C · rs1489785243 · VCV2103352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5403 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mucopolysaccharidosis type 3B

Computational evidence

Protein change
AlphaMissense	0.5403	ambiguous
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -14.94	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,962 bp · p 0.0079 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 0.000657% 1/152,258 alleles · very rare

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.Arg149Pro
Coding: c.446G>C
MANE Select: NM_000263
dbSNP: rs1489785243
Type: single nucleotide variant
Location: chr17:42537460 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 1 PDB
Residue 149: an α-helix

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.Arg149Leu Uncertain significance ★★ ⚠ same residue
NAGLU p.Arg149fs Pathogenic ★ same residue
NAGLU p.Arg149Cys 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-arg149pro (accessed [today's date]).

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