# NM_000487.6(ARSA):c.937dup (p.Arg313fs)

https://sugi.bio/variant/arsa-p-arg313fs

## Summary

**ARSA p.Arg313fs (c.937dup)** is classified **Likely pathogenic** in ARSA (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant; Associated with metachromatic leukodystrophy.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2518326922 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ARSA gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to metachromatic leukodystrophy.

*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) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 37 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ARSA is a diagnostic-grade gene on 23 Genomics England panels |

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

- Periventricular leukomalacia — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Hearing impairment — Frequent (79-30%)
- Visual impairment — Frequent (79-30%)
- Abnormality of visual evoked potentials — Frequent (79-30%)
- Decreased nerve conduction velocity — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Ataxia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003230/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ARSA](https://sugi.bio/atlas/gene/ARSA/) |
| Protein change (HGVS p.) | p.Arg313fs |
| Coding change (HGVS c.) | c.937dup |
| MANE Select transcript | [NM_000487](https://www.ncbi.nlm.nih.gov/nuccore/NM_000487) |
| dbSNP | [rs2518326922](https://www.ncbi.nlm.nih.gov/snp/rs2518326922/) |
| Variant type | Duplication |
| Location | chr22:50626195-50626196 (GRCh38) |
| ClinVar | [VCV2501673](https://www.ncbi.nlm.nih.gov/clinvar/variation/2501673/) |

**All HGVS expressions:** `NC_000022.10:g.51064625dup`, `NC_000022.11:g.50626197dup`, `NG_009260.2:g.6984dup`, `NM_000487.6:c.937dup`, `NM_000487.6:c.937dupC`, `NM_001085425.3:c.937dup`, `NM_001085426.3:c.937dup`, `NM_001085427.3:c.937dup`, `NM_001085428.3:c.679dup`, `NM_001362782.2:c.679dup`

## 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 7.529, GERP 2.03, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.166, pLI 1.511e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 8**, so the transcript is predicted to undergo NMD.
- 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: **no gnomAD frequency available for this variant** — 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}

**ARSA** population constraint: LOEUF 1.166, pLI 1.511e-10, missense-Z -0.56045. *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):

- **metachromatic leukodystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **313** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 96.43, 95% of residues very-high.

**10 experimental structure(s)** (PDB): [1AUK](https://www.rcsb.org/structure/1AUK), [1E1Z](https://www.rcsb.org/structure/1E1Z), [1E2S](https://www.rcsb.org/structure/1E2S), [1E33](https://www.rcsb.org/structure/1E33), [1E3C](https://www.rcsb.org/structure/1E3C), [1N2K](https://www.rcsb.org/structure/1N2K) — incl. mutant structure 1E1Z.

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

*Describes the biological roles of ARSA (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:** ARSA's established molecular role includes calcium ion binding.


### Pathways affected {#pathways}

ARSA participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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:** calcium ion binding, sulfuric ester hydrolase activity.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lifecell International Pvt. Ltd | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[metachromatic leukodystrophy](https://sugi.bio/atlas/disease/metachromatic-leukodystrophy/).

**Reported phenotype names (ClinVar):** Metachromatic leukodystrophy, Cerebral sclerosis diffuse metachromatic form, ARSA DEFICIENCY, CEREBROSIDE SULFATASE DEFICIENCY, Arylsulfatase A Deficiency, METACHROMATIC LEUKOENCEPHALOPATHY, SULFATIDE LIPIDOSIS.

## Same-residue context {#hotspot}

Residue **313** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [ARSA p.Arg313Gly](/variant/arsa-p-arg313gly), [ARSA p.Arg313Pro](/variant/arsa-p-arg313pro), [ARSA p.Arg313Ter](/variant/arsa-p-arg313ter), [ARSA p.Arg313Gln](/variant/arsa-p-arg313gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ARSA variant pages (same residue, condition, or type): [ARSA p.Arg313Gln](/variant/arsa-p-arg313gln), [ARSA p.Arg313Gly](/variant/arsa-p-arg313gly), [ARSA p.Arg313Ter](/variant/arsa-p-arg313ter), [ARSA p.Arg313Leu](/variant/arsa-p-arg313leu), [ARSA p.Arg313=](/variant/arsa-p-arg313), [ARSA p.Arg313Pro](/variant/arsa-p-arg313pro), [ARSA p.Arg498fs](/variant/arsa-p-arg498fs), [ARSA p.Arg99fs](/variant/arsa-p-arg99fs).

### 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 2501673). 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.*