# NM_000046.5(ARSB):c.1391C>A (p.Ser464Ter)

https://sugi.bio/variant/arsb-p-ser464ter

## Summary

**ARSB p.Ser464Ter (c.1391C>A)** is classified **Likely pathogenic** in ARSB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-01). Absent from gnomAD v4.1; Associated with mucopolysaccharidosis type 6.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs769996056 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ARSB gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to mucopolysaccharidosis type 6.

*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 (Europe) |
| Clinical trials | 15 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ARSB is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Mucopolysaccharidosis type 6** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Thick lower lip vermilion — Very frequent (99-80%)
- Sinusitis — Very frequent (99-80%)
- Coarse facial features — Very frequent (99-80%)
- Chronic otitis media — Very frequent (99-80%)
- Abnormal metaphysis morphology — Very frequent (99-80%)
- Joint stiffness — Very frequent (99-80%)
- Failure to thrive — Very frequent (99-80%)
- Epiphyseal dysplasia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007095/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ARSB](https://sugi.bio/atlas/gene/ARSB/) |
| Protein change (HGVS p.) | p.Ser464Ter |
| Coding change (HGVS c.) | c.1391C>A |
| MANE Select transcript | [NM_020427](https://www.ncbi.nlm.nih.gov/nuccore/NM_020427) (variant reported on NM_000046) |
| dbSNP | [rs769996056](https://www.ncbi.nlm.nih.gov/snp/rs769996056/) |
| Variant type | single nucleotide variant |
| Location | chr5:78780608-78780608 (GRCh38) |
| ClinVar | [VCV559710](https://www.ncbi.nlm.nih.gov/clinvar/variation/559710/) |

**All HGVS expressions:** `NC_000005.10:g.78780608G>T`, `NC_000005.9:g.78076431G>T`, `NG_007089.1:g.210927C>A`, `NM_000046.5:c.1391C>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 9.955, GERP 1.84, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 38.0**. 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.*
- 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}

**ARSB** population constraint: ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 6** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.32, 47% of residues very-high.

**2 experimental structure(s)** (PDB): [6ZZE](https://www.rcsb.org/structure/6ZZE), [6ZZF](https://www.rcsb.org/structure/6ZZF).

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

*Describes the biological roles of ARSB (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:** ARSB's established molecular role includes acetylcholine receptor activator activity.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** acetylcholine receptor activator activity.

**Biological process:** negative regulation of cell population proliferation, negative regulation of cell migration, urokinase plasminogen activator signaling pathway.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-01.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Likely pathogenic | criteria provided, single submitter | curation | 2018-01-01 |

## Associated conditions {#conditions}

[mucopolysaccharidosis type 6](https://sugi.bio/atlas/disease/mucopolysaccharidosis-type-6/).

**Reported phenotype names (ClinVar):** Mucopolysaccharidosis type 6, N-ACETYLGALACTOSAMINE-4-SULFATASE DEFICIENCY, MPS VI, MPS 6, Maroteaux Lamy syndrome, ARSB DEFICIENCY, ARYLSULFATASE B DEFICIENCY.

## Same-residue context {#hotspot}

Residue **464** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ARSB p.Ser464fs](/variant/arsb-p-ser464fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ARSB variant pages (same residue, condition, or type): [ARSB p.Ser464fs](/variant/arsb-p-ser464fs), [ARSB p.Ser464Leu](/variant/arsb-p-ser464leu), [ARSB c.1142+1G>A](/variant/arsb-c-1142-plus-1g-a), [ARSB c.1142+1G>T](/variant/arsb-c-1142-plus-1g-t), [ARSB c.1142+2T>A](/variant/arsb-c-1142-plus-2t-a), [ARSB c.1142+2T>C](/variant/arsb-c-1142-plus-2t-c), [ARSB c.1143-1G>A](/variant/arsb-c-1143-minus-1g-a), [ARSB c.1143-1G>C](/variant/arsb-c-1143-minus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 559710). 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.*