# NM_000049.4(ASPA):c.170C>T (p.Ala57Val)

https://sugi.bio/variant/aspa-p-ala57val

## Summary

**ASPA p.Ala57Val (c.170C>T)** is classified **Likely pathogenic** in ASPA (ClinVar, Single submitter, 2 submitters; last evaluated 2024-07-08). AlphaMissense: likely pathogenic (0.944); Absent from gnomAD v4.1; Associated with Canavan disease.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1555538148 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ASPA gene that is considered likely disease-causing, submitted by 2 submitters, 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.Ala57Val |
| Coding change (HGVS c.) | c.170C>T |
| MANE Select transcript | [NM_000049](https://www.ncbi.nlm.nih.gov/nuccore/NM_000049) |
| dbSNP | [rs1555538148](https://www.ncbi.nlm.nih.gov/snp/rs1555538148/) |
| Variant type | single nucleotide variant |
| Location | chr17:3476329-3476329 (GRCh38) |
| ClinVar | [VCV556428](https://www.ncbi.nlm.nih.gov/clinvar/variation/556428/) |

**All HGVS expressions:** `NC_000017.10:g.3379623C>T`, `NC_000017.11:g.3476329C>T`, `NG_008399.2:g.7684C>T`, `NG_008399.3:g.7221C>T`, `NM_000049.4:c.170C>T`, `NM_001128085.1:c.170C>T`, `NM_001321336.2:c.-73-6931G>A`, `NM_001321337.2:c.-73-6931G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.944) — concordant with the pathogenic call
- REVEL 0.973 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.162 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.21) — consistent with the pathogenic call
- Conservation: phyloP 7.657, GERP 1.71, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in ASPA (of 1,867 modeled).
- CADD: **PHRED 29.9**. 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 0.86** across the covering region of the MANE Select transcript (3,476,160–3,499,085), spanning 22,925 bp. Chi-square p 0.0073. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.21**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.21**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **57** lies in a UniProt-annotated variant site (in cand); a UniProt-annotated variant site (in cand; <1% residual enzyme activity); 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-08.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 2 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2018-02-05 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-08 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **57** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ASPA p.Ala57Ser](/variant/aspa-p-ala57ser), [ASPA p.Ala57Thr](/variant/aspa-p-ala57thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ASPA variant pages (same residue, condition, or type): [ASPA p.Ala57Thr](/variant/aspa-p-ala57thr), [ASPA p.Ala57Ser](/variant/aspa-p-ala57ser), [ASPA p.Ala57=](/variant/aspa-p-ala57), [ASPA c.236+2T>C](/variant/aspa-c-236-plus-2t-c), [ASPA c.237-1G>T](/variant/aspa-c-237-minus-1g-t), [ASPA c.237-2A>T](/variant/aspa-c-237-minus-2a-t), [ASPA c.527-1G>A](/variant/aspa-c-527-minus-1g-a), [ASPA c.527-2A>C](/variant/aspa-c-527-minus-2a-c).

### 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 556428). 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.*