# NM_000487.6(ARSA):c.434G>C (p.Arg145Pro)

https://sugi.bio/variant/arsa-p-arg145pro

## Summary

**ARSA p.Arg145Pro (c.434G>C)** is classified **Uncertain significance** in ARSA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the ARSA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Arg145Pro |
| Coding change (HGVS c.) | c.434G>C |
| MANE Select transcript | [NM_000487](https://www.ncbi.nlm.nih.gov/nuccore/NM_000487) |
| Variant type | single nucleotide variant |
| Location | chr22:50627197-50627197 (GRCh38) |
| ClinVar | [VCV4585531](https://www.ncbi.nlm.nih.gov/clinvar/variation/4585531/) |

**All HGVS expressions:** `NC_000022.10:g.51065625C>G`, `NC_000022.11:g.50627197C>G`, `NG_009260.2:g.5983G>C`, `NG_146552.1:g.968C>G`, `NM_000487.6:c.434G>C`, `NM_001085425.3:c.434G>C`, `NM_001085426.3:c.434G>C`, `NM_001085427.3:c.434G>C`, `NM_001085428.3:c.176G>C`, `NM_001362782.2:c.176G>C`

## 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 **donor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.268, GERP 2.02, phastCons 0.998 — highly conserved position (PP3-type support)
- CADD: **PHRED 27.8**. 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.*
- Regional missense constraint: **o/e 1.00** across the covering region of the MANE Select transcript (50,625,148–50,627,779), spanning 2,631 bp. Chi-square p 0.96. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.23**, acceptor gain **0.12**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.03**, donor loss **0.23**, acceptor gain **0.12**, donor gain **0.00**.
- Pangolin: Δ**0.32** (loss), gain 0.18 / loss 0.32. 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 (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,562 in the highest group · 1/1,460,534 alleles overall — very rare (popmax 8.48e-05%, 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}

**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 **145** lies in a β-strand.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-06 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Same-residue context {#hotspot}

Residue **145** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [ARSA p.Arg145fs](/variant/arsa-p-arg145fs), [ARSA p.Arg145Gly](/variant/arsa-p-arg145gly), [ARSA p.Arg145Ter](/variant/arsa-p-arg145ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ARSA variant pages (same residue, condition, or type): [ARSA p.Arg145Gly](/variant/arsa-p-arg145gly), [ARSA p.Arg145Ter](/variant/arsa-p-arg145ter), [ARSA p.Arg145Gln](/variant/arsa-p-arg145gln), [ARSA p.Arg290His](/variant/arsa-p-arg290his), [ARSA p.Gly327Ser](/variant/arsa-p-gly327ser), [ARSA p.Pro138Arg](/variant/arsa-p-pro138arg), [ARSA p.Arg216Cys](/variant/arsa-p-arg216cys), [ARSA p.Arg498Cys](/variant/arsa-p-arg498cys).

### 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 4585531). 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.*