Is NAGLU p.Pro516Ser (c.1546C>T) pathogenic?

NAGLU p.Pro516Ser (c.1546C>T) is classified Uncertain significance in NAGLU (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-15). AlphaMissense: ambiguous (0.452); Very rare (popmax 8.48e-05%, nfe); Associated with mucopolysaccharidosis type 3B.

What condition is associated with NAGLU p.Pro516Ser (c.1546C>T)?

NAGLU p.Pro516Ser (c.1546C>T) is associated with mucopolysaccharidosis type 3B (ClinVar).

How common is NAGLU p.Pro516Ser (c.1546C>T) in the general population?

NAGLU p.Pro516Ser (c.1546C>T) is very rare (popmax 8.48e-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.Pro516Ser (c.1546C>T)?

AlphaMissense predicts ambiguous (score 0.452) — an in-silico prediction, not a clinical call.

NAGLU p.Pro516Ser

c.1546C>T · rs1599261339 · VCV635304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.452 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mucopolysaccharidosis type 3B

Computational evidence

Protein change
AlphaMissense	0.452	ambiguous
REVEL	0.685	pathogenic-leaning
SaProt	LLR -6.06	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,962 bp · p 0.0079 · regional, not allelic
Overall
CADD	24.5	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 8.48e-05% European (non-Finnish) · 1/1,179,454 alleles

Overall 6.85e-05% 1/1,458,846 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.Pro516Ser
Coding: c.1546C>T
MANE Select: NM_000263
dbSNP: rs1599261339
Type: single nucleotide variant
Location: chr17:42543552 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 1 PDB
Residue 516: an α-helix; a UniProt-annotated variant site (in mps3b); a UniProt-annotated variant site (in mps3b; no enzyme activity)

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

For Mucopolysaccharidosis type 3 (Orphanet):

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

Similar variants

NAGLU p.Pro516Leu Likely pathogenic ★★ ⚠ same residue
NAGLU p.Pro516= Likely benign ★★ 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-pro516ser (accessed [today's date]).

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