# NM_000046.5(ARSB):c.1381G>T (p.Glu461Ter)

https://sugi.bio/variant/arsb-p-glu461ter

## Summary

**ARSB p.Glu461Ter (c.1381G>T)** is classified **Likely pathogenic** in ARSB (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-13). Absent from gnomAD v4.1; Associated with mucopolysaccharidosis type 6.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2112617391 · 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.Glu461Ter |
| Coding change (HGVS c.) | c.1381G>T |
| MANE Select transcript | [NM_020427](https://www.ncbi.nlm.nih.gov/nuccore/NM_020427) (variant reported on NM_000046) |
| dbSNP | [rs2112617391](https://www.ncbi.nlm.nih.gov/snp/rs2112617391/) |
| Variant type | single nucleotide variant |
| Location | chr5:78780618-78780618 (GRCh38) |
| ClinVar | [VCV1323934](https://www.ncbi.nlm.nih.gov/clinvar/variation/1323934/) |

**All HGVS expressions:** `NC_000005.10:g.78780618C>A`, `NC_000005.9:g.78076441C>A`, `NG_007089.1:g.210917G>T`, `NM_000046.5:c.1381G>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.28) — consistent with the pathogenic call
- Conservation: phyloP 3.305, GERP 1.84, phastCons 0.983 — 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 39.0**. 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 deltas (raw): acceptor loss **0.28**, donor loss **0.00**, acceptor gain **0.13**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.28**, donor loss **0.00**, acceptor gain **0.13**, donor gain **0.00**.
- Pangolin: Δ**0.35** (loss), gain 0.10 / loss 0.35. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- 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 2020-11-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-11-13 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ARSB variant pages (same residue, condition, or type): [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), [ARSB c.1143-8T>G](/variant/arsb-c-1143-minus-8t-g), [ARSB c.1213+6T>C](/variant/arsb-c-1213-plus-6t-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 1323934). 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.*