# NM_000046.5(ARSB):c.121dup (p.Ala41fs)

https://sugi.bio/variant/arsb-p-ala41fs

## Summary

**ARSB p.Ala41fs (c.121dup)** is classified **Pathogenic/Likely pathogenic** in ARSB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-24). Very rare (popmax 0.000539%, nfe); Associated with mucopolysaccharidosis type 6.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1561197865 · 3 submitters · 1 linked condition · very rare (popmax 0.000539%, nfe)

## For patients & families {#patients}

This is a change in the ARSB gene that is considered likely disease-causing, submitted by 3 submitters, 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.Ala41fs |
| Coding change (HGVS c.) | c.121dup |
| MANE Select transcript | [NM_020427](https://www.ncbi.nlm.nih.gov/nuccore/NM_020427) (variant reported on NM_000046) |
| dbSNP | [rs1561197865](https://www.ncbi.nlm.nih.gov/snp/rs1561197865/) |
| Variant type | Duplication |
| Location | chr5:78985127-78985128 (GRCh38) |
| ClinVar | [VCV1074870](https://www.ncbi.nlm.nih.gov/clinvar/variation/1074870/) |

**All HGVS expressions:** `NC_000005.10:g.78985131dup`, `NC_000005.9:g.78280954dup`, `NG_007089.1:g.6407dup`, `NM_000046.3:c.121dupG`, `NM_000046.4:c.121dupG`, `NM_000046.5:c.121dup`, `NM_198709.3:c.121dup`

## 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 3.33, GERP -2.51, phastCons 0.763 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — 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 22.8**. 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** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000539%** (nfe) · FAF95 0.000194% · FAF99 0.000127% · 6/1,113,150 in the highest group · 6/1,478,226 alleles overall — very rare (popmax 0.000539%, nfe).

*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}

Residue **41** lies in the upar/ly6 domain; a β-strand; a disulfide bond.

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. p.Ala41fs falls in the upar/ly6 domain.


### 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-24.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-08-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-21 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-24 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ARSB variant pages (same residue, condition, or type): [ARSB p.Arg434Ter](/variant/arsb-p-arg434ter), [ARSB p.Pro123fs](/variant/arsb-p-pro123fs), [ARSB p.Ser120fs](/variant/arsb-p-ser120fs), [ARSB p.Val22fs](/variant/arsb-p-val22fs), [ARSB c.-310-3dup](/variant/arsb-c-minus-310-minus-3dup), [ARSB p.Ala267fs](/variant/arsb-p-ala267fs), [ARSB p.Arg388fs](/variant/arsb-p-arg388fs), [ARSB p.His430fs](/variant/arsb-p-his430fs).

### 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 1074870). 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.*