# NM_000263.4(NAGLU):c.1391G>C (p.Arg464Pro)

https://sugi.bio/variant/naglu-p-arg464pro

## Summary

**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.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs377282648 · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the NAGLU gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to mucopolysaccharidosis type 3B.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Brazil) |
| Clinical trials | 15 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NAGLU is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Mucopolysaccharidosis type 3** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Chronic otitis media — Very frequent (99-80%)
- Delayed speech and language development — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)
- Coarse hair — Very frequent (99-80%)
- Generalized hirsutism — Very frequent (99-80%)
- Progressive neurologic deterioration — Very frequent (99-80%)
- Sleep abnormality — Very frequent (99-80%)
- Urinary glycosaminoglycan excretion — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007072/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NAGLU](https://sugi.bio/atlas/gene/NAGLU/) |
| Protein change (HGVS p.) | p.Arg464Pro |
| Coding change (HGVS c.) | c.1391G>C |
| MANE Select transcript | [NM_000263](https://www.ncbi.nlm.nih.gov/nuccore/NM_000263) |
| dbSNP | [rs377282648](https://www.ncbi.nlm.nih.gov/snp/rs377282648/) |
| Variant type | single nucleotide variant |
| Location | chr17:42543397-42543397 (GRCh38) |
| ClinVar | [VCV2001140](https://www.ncbi.nlm.nih.gov/clinvar/variation/2001140/) |

**All HGVS expressions:** `NC_000017.10:g.40695415G>C`, `NC_000017.11:g.42543397G>C`, `NG_011552.1:g.12465G>C`, `NM_000263.4:c.1391G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7472)
- REVEL 0.888 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.103 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 4.029, GERP 1.33, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.6**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (42,536,273–42,544,235), spanning 7,962 bp. Chi-square p 0.0079. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**NAGLU** population constraint: LOEUF 1.029, pLI 2.3821e-09, missense-Z 0.096459. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mucopolysaccharidosis type 3B** — Definitive (AR)

## Protein context {#protein}

Residue **464** lies in a UniProt-annotated variant site (in mps3b).

AlphaFold model confidence (whole protein): pLDDT 97.19, 97% of residues very-high.

**1 experimental structure(s)** (PDB): [4XWH](https://www.rcsb.org/structure/4XWH).

## What this gene does {#gene-function}

*Describes the biological roles of NAGLU (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** NAGLU participates in disease-associated pathways. In Reactome, NAGLU is annotated in disease pathway(s) including **MPS IIIB - Sanfilippo syndrome B**.

**Disease mechanism (Reactome):** NAGLU loss or alteration is curated in [MPS IIIB - Sanfilippo syndrome B](https://reactome.org/content/detail/R-HSA-2206282).

### Pathways affected {#pathways}

NAGLU participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [MPS IIIB - Sanfilippo syndrome B](https://reactome.org/content/detail/R-HSA-2206282) | curated |
| [HS-GAG degradation](https://reactome.org/content/detail/R-HSA-2024096) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-28 |

## Associated conditions {#conditions}

[mucopolysaccharidosis type 3B](https://sugi.bio/atlas/disease/mucopolysaccharidosis-type-3b/), [Charcot-Marie-Tooth disease axonal type 2V](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-axonal-type-2v/).

**Reported phenotype names (ClinVar):** Mucopolysaccharidosis, MPS-III-B, Charcot-Marie-Tooth disease axonal type 2V, N-ACETYL-ALPHA-D-GLUCOSAMINIDASE DEFICIENCY, NAGLU DEFICIENCY, SANFILIPPO SYNDROME B, MUCOPOLYSACCHARIDOSIS, TYPE IIIB, MPS III B, Mucopolysaccharidosis type IIIB (Sanfilippo B), CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2V, CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2V.

## Same-residue context {#hotspot}

Residue **464** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NAGLU p.Arg464Ter](/variant/naglu-p-arg464ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NAGLU variant pages (same residue, condition, or type): [NAGLU p.Arg464Ter](/variant/naglu-p-arg464ter), [NAGLU p.Arg464Gln](/variant/naglu-p-arg464gln), [NAGLU c.1021+1G>A](/variant/naglu-c-1021-plus-1g-a), [NAGLU c.1022-2A>G](/variant/naglu-c-1022-minus-2a-g), [NAGLU c.383+1G>T](/variant/naglu-c-383-plus-1g-t), [NAGLU c.384-1G>A](/variant/naglu-c-384-minus-1g-a), [NAGLU c.531+1G>A](/variant/naglu-c-531-plus-1g-a), [NAGLU c.531+1G>C](/variant/naglu-c-531-plus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2001140). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*