Is NAGLU p.Pro258Ser (c.772C>T) pathogenic?

NAGLU p.Pro258Ser (c.772C>T) is classified Uncertain significance in NAGLU (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely benign (0.2031); Very rare (popmax 0.00333%, amr); Associated with Charcot-Marie-Tooth disease axonal type 2V.

What condition is associated with NAGLU p.Pro258Ser (c.772C>T)?

NAGLU p.Pro258Ser (c.772C>T) is associated with Charcot-Marie-Tooth disease axonal type 2V, mucopolysaccharidosis type 3B (ClinVar).

How common is NAGLU p.Pro258Ser (c.772C>T) in the general population?

NAGLU p.Pro258Ser (c.772C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about NAGLU p.Pro258Ser (c.772C>T)?

AlphaMissense predicts likely benign (score 0.2031) — an in-silico prediction, not a clinical call.

NAGLU p.Pro258Ser

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.772C>T · rs1160168612 · VCV1924721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2V

Computational evidence

Protein change
AlphaMissense	0.2031	likely benign
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -11.71	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,962 bp · p 0.0079 · regional, not allelic
Overall
CADD	26.5	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 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,166 alleles · very rare exomes 2/1,461,894 · genomes 0/152,272 · joint denominator

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.Pro258Ser
Coding: c.772C>T
MANE Select: NM_000263
dbSNP: rs1160168612
Type: single nucleotide variant
Location: chr17:42540957 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 1 PDB
Residue 258: 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 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
NAGLU p.Arg130Cys 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-pro258ser (accessed [today's date]).

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