# NM_000487.6(ARSA):c.1254C>T (p.Ala418=)

https://sugi.bio/variant/arsa-p-ala418

## Summary

**ARSA p.Ala418= (c.1254C>T)** is classified **Likely benign** in ARSA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-07). Very rare (popmax 0.00112%, sas); Associated with metachromatic leukodystrophy.

**At a glance:** Likely benign · review: Single submitter · rsID rs2518322568 · 1 submitter · 1 linked condition · very rare (popmax 0.00112%, sas)

## For patients & families {#patients}

This is a change in the ARSA gene that is classified as likely benign — not considered 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.Ala418= |
| Coding change (HGVS c.) | c.1254C>T |
| MANE Select transcript | [NM_000487](https://www.ncbi.nlm.nih.gov/nuccore/NM_000487) |
| dbSNP | [rs2518322568](https://www.ncbi.nlm.nih.gov/snp/rs2518322568/) |
| Variant type | single nucleotide variant |
| Location | chr22:50625421-50625421 (GRCh38) |
| ClinVar | [VCV2904004](https://www.ncbi.nlm.nih.gov/clinvar/variation/2904004/) |

**All HGVS expressions:** `NC_000022.10:g.51063849G>A`, `NC_000022.11:g.50625421G>A`, `NG_009260.2:g.7759C>T`, `NM_000487.6:c.1254C>T`, `NM_001085425.3:c.1254C>T`, `NM_001085426.3:c.1254C>T`, `NM_001085427.3:c.1254C>T`, `NM_001085428.3:c.996C>T`, `NM_001362782.2:c.996C>T`

## Computational & population evidence {#evidence}

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

- **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 gain** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.223, GERP -4.66 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.18**. 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 **0.06**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00112%** (sas) · 1/89,262 in the highest group · 2/1,443,742 alleles overall — very rare (popmax 0.00112%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00112% | 89,262 |
| European (non-Finnish) | 8.56e-05% | 1,168,816 |

*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}


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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-07 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ARSA variant pages (same residue, condition, or type): [ARSA p.Ala418Thr](/variant/arsa-p-ala418thr), [ARSA p.Ala418Val](/variant/arsa-p-ala418val), [ARSA c.1107+1G>A](/variant/arsa-c-1107-plus-1g-a), [ARSA c.1107+1G>T](/variant/arsa-c-1107-plus-1g-t), [ARSA c.1108-2A>G](/variant/arsa-c-1108-minus-2a-g), [ARSA c.1108-3C>G](/variant/arsa-c-1108-minus-3c-g), [ARSA c.1210+1G>A](/variant/arsa-c-1210-plus-1g-a), [ARSA c.224+1G>A](/variant/arsa-c-224-plus-1g-a).

### 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 2904004). 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.*