# NM_000049.4(ASPA):c.291del (p.His98fs)

https://sugi.bio/variant/aspa-p-his98fs

## Summary

**ASPA p.His98fs (c.291del)** is classified **Pathogenic** in ASPA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-30). No gnomAD frequency available for this variant; Associated with Canavan disease.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2543619403 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ASPA gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Canavan disease.

*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, Infancy, Neonatal |
| Clinical trials | 11 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ASPA is a diagnostic-grade gene on 12 Genomics England panels |

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

- Optic atrophy — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- EEG abnormality — Very frequent (99-80%)
- Reduced consciousness/confusion — Very frequent (99-80%)
- Feeding difficulties in infancy — Very frequent (99-80%)
- Cognitive impairment — Very frequent (99-80%)
- Macrocephaly — Frequent (79-30%)
- Hearing impairment — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005984/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ASPA](https://sugi.bio/atlas/gene/ASPA/) |
| Protein change (HGVS p.) | p.His98fs |
| Coding change (HGVS c.) | c.291del |
| MANE Select transcript | [NM_000049](https://www.ncbi.nlm.nih.gov/nuccore/NM_000049) |
| dbSNP | [rs2543619403](https://www.ncbi.nlm.nih.gov/snp/rs2543619403/) |
| Variant type | Deletion |
| Location | chr17:3481657-3481657 (GRCh38) |
| ClinVar | [VCV2000932](https://www.ncbi.nlm.nih.gov/clinvar/variation/2000932/) |

**All HGVS expressions:** `NC_000017.10:g.3384951del`, `NC_000017.11:g.3481657del`, `NG_008399.2:g.13012del`, `NG_008399.3:g.12549del`, `NM_000049.4:c.291del`, `NM_001128085.1:c.291del`, `NM_001321336.2:c.-73-12259del`, `NM_001321337.2:c.-73-12259del`

## 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 6.994, GERP 1.86, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.098, pLI 4.2807e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 6**, so the transcript is predicted to undergo NMD.
- 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: **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}

**ASPA** population constraint: LOEUF 1.098, pLI 4.2807e-05, missense-Z 1.2489; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **Canavan disease** — Definitive (AR)

## Protein context {#protein}

Residue **98** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.14, 94% of residues very-high.

**8 experimental structure(s)** (PDB): [2I3C](https://www.rcsb.org/structure/2I3C), [2O4H](https://www.rcsb.org/structure/2O4H), [2O53](https://www.rcsb.org/structure/2O53), [2Q51](https://www.rcsb.org/structure/2Q51), [4MRI](https://www.rcsb.org/structure/4MRI), [4MXU](https://www.rcsb.org/structure/4MXU) — incl. mutant structure 4MRI.

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

*Describes the biological roles of ASPA (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:** ASPA's established molecular role includes aspartoacylase activity.


### Pathways affected {#pathways}

ASPA participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Aspartate and asparagine metabolism](https://reactome.org/content/detail/R-HSA-8963693) | curated |

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

**Molecular function:** aspartoacylase activity, identical protein binding.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-30.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-30 |

## Associated conditions {#conditions}

[Canavan disease](https://sugi.bio/atlas/disease/canavan-disease/).

**Reported phenotype names (ClinVar):** Spongy degeneration of central nervous system, Canavan disease, Von Bogaert-Bertrand disease, ACY2 DEFICIENCY, AMINOACYLASE 2 DEFICIENCY, ASP DEFICIENCY, ASPA DEFICIENCY, ASPARTOACYLASE DEFICIENCY, CANAVAN-VAN BOGAERT-BERTRAND DISEASE.

## Similar variants {#similar}

Related ASPA variant pages (same residue, condition, or type): [ASPA p.Asp204fs](/variant/aspa-p-asp204fs), [ASPA p.Cys152fs](/variant/aspa-p-cys152fs), [ASPA p.Cys276fs](/variant/aspa-p-cys276fs), [ASPA p.Gln12fs](/variant/aspa-p-gln12fs), [ASPA p.Glu129fs](/variant/aspa-p-glu129fs), [ASPA p.Ile11fs](/variant/aspa-p-ile11fs), [ASPA p.Lys103fs](/variant/aspa-p-lys103fs), [ASPA p.Met82fs](/variant/aspa-p-met82fs).

### 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 2000932). 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.*