# NM_001012301.4(ARSI):c.908del (p.Phe303fs)

https://sugi.bio/variant/arsi-p-phe303fs

## Summary

**ARSI p.Phe303fs (c.908del)** is classified **Uncertain significance** in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-14). Very rare (popmax 0.00133%, afr); Associated with Spastic paraplegia.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs771488404 · 1 submitter · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

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

*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 | [ARSI](https://sugi.bio/atlas/gene/ARSI/) |
| Protein change (HGVS p.) | p.Phe303fs |
| Coding change (HGVS c.) | c.908del |
| MANE Select transcript | [NM_001012301](https://www.ncbi.nlm.nih.gov/nuccore/NM_001012301) |
| dbSNP | [rs771488404](https://www.ncbi.nlm.nih.gov/snp/rs771488404/) |
| Variant type | Deletion |
| Location | chr5:150298016-150298016 (GRCh38) |
| ClinVar | [VCV1051779](https://www.ncbi.nlm.nih.gov/clinvar/variation/1051779/) |

**All HGVS expressions:** `NC_000005.10:g.150298018del`, `NC_000005.9:g.149677581del`, `NG_051250.1:g.9947del`, `NM_001012301.4:c.908del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 2.949, GERP -2.21, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.403, pLI 4.8294e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 34.0**. 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** — the release is built from a substitutions-only source, so it holds no deletion 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 **0.00133%** (afr) · FAF95 0.000688% · FAF99 0.000539% · 1/74,922 in the highest group · 16/1,612,472 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,470 |
| African / African-American (grpmax) | 0.00133% | 74,922 |
| European (non-Finnish) | 0.00119% | 84,287 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ARSI** population constraint: LOEUF 1.403, pLI 4.8294e-07, missense-Z 0.89049. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.35, 77% of residues very-high.

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

*Describes the biological roles of ARSI (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.*


### Pathways affected {#pathways}

ARSI participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [The activation of arylsulfatases](https://reactome.org/content/detail/R-HSA-1663150) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-03-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-03-14 |

## Associated conditions {#conditions}

[Spastic paraplegia](https://sugi.bio/atlas/disease/spastic-paraplegia/).

**Reported phenotype names (ClinVar):** Spastic paraplegia.

## Similar variants {#similar}

Related ARSI variant pages (same residue, condition, or type): [ARSI p.Ala216Thr](/variant/arsi-p-ala216thr), [ARSI p.Ala259Val](/variant/arsi-p-ala259val), [ARSI p.Ala264Thr](/variant/arsi-p-ala264thr), [ARSI p.Ala399Asp](/variant/arsi-p-ala399asp), [ARSI p.Ala414Ser](/variant/arsi-p-ala414ser), [ARSI p.Ala414Thr](/variant/arsi-p-ala414thr), [ARSI p.Ala78Thr](/variant/arsi-p-ala78thr), [ARSI p.Arg117Cys](/variant/arsi-p-arg117cys).

### 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 1051779). 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.*