# NM_000046.5(ARSB):c.194C>T (p.Ser65Phe)

https://sugi.bio/variant/arsb-p-ser65phe

## Summary

**ARSB p.Ser65Phe (c.194C>T)** is classified **Conflicting classifications of pathogenicity** in ARSB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-10). AlphaMissense: likely pathogenic (0.6498); No allele count reported in gnomAD v4.1 (AN 1,541,968); Associated with mucopolysaccharidosis type 6.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1233331806 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,541,968)

## For patients & families {#patients}

This is a change in the ARSB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 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 14 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.Ser65Phe |
| Coding change (HGVS c.) | c.194C>T |
| MANE Select transcript | [NM_000046](https://www.ncbi.nlm.nih.gov/nuccore/NM_000046) |
| dbSNP | [rs1233331806](https://www.ncbi.nlm.nih.gov/snp/rs1233331806/) |
| Variant type | single nucleotide variant |
| Location | chr5:78985055-78985055 (GRCh38) |
| ClinVar | [VCV559735](https://www.ncbi.nlm.nih.gov/clinvar/variation/559735/) |

**All HGVS expressions:** `NC_000005.10:g.78985055G>A`, `NC_000005.9:g.78280878G>A`, `NG_007089.1:g.6480C>T`, `NM_000046.5:c.194C>T`, `NM_198709.3:c.194C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6498)
- REVEL 0.955 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.966 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.229, GERP 0.634, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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: **no allele count reported in gnomAD v4.1 (AN 1,541,968)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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: LOEUF 1.032, pLI 6.1124e-13, missense-Z -0.052327. *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 **65** lies in a UniProt-annotated variant site (in mps6; intermediate form).

AlphaFold model confidence (whole protein): pLDDT 93.74, 90% of residues very-high.

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

## 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 N-acetylgalactosamine-4-sulfatase activity. In Reactome, ARSB is annotated in disease pathway(s) including **MPS VI - Maroteaux-Lamy syndrome**.

**Disease mechanism (Reactome):** ARSB loss or alteration is curated in [MPS VI - Maroteaux-Lamy syndrome](https://reactome.org/content/detail/R-HSA-2206285).

### Pathways affected {#pathways}

ARSB participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [MPS VI - Maroteaux-Lamy syndrome](https://reactome.org/content/detail/R-HSA-2206285) | curated |
| [CS/DS degradation](https://reactome.org/content/detail/R-HSA-2024101) | curated |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [The activation of arylsulfatases](https://reactome.org/content/detail/R-HSA-1663150) | curated |

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

**Molecular function:** N-acetylgalactosamine-4-sulfatase activity.

**Biological process:** regulation of epithelial cell migration, chondroitin sulfate proteoglycan catabolic process, colon epithelial cell migration.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-02-10.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Uncertain significance | criteria provided, single submitter | curation | 2018-01-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-10 |

## 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.

## 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 2026-10-14); 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 559735). 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.*