# NM_000049.4(ASPA):c.807G>A (p.Thr269=)

https://sugi.bio/variant/aspa-p-thr269

## Summary

**ASPA p.Thr269= (c.807G>A)** is classified **Conflicting classifications of pathogenicity** in ASPA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-02). Very rare (popmax 0.0061%, nfe); Associated with Canavan disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs759106494 · 3 submitters · 1 linked condition · very rare (popmax 0.0061%, nfe)

## For patients & families {#patients}

This is a change in the ASPA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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.Thr269= |
| Coding change (HGVS c.) | c.807G>A |
| MANE Select transcript | [NM_000049](https://www.ncbi.nlm.nih.gov/nuccore/NM_000049) |
| dbSNP | [rs759106494](https://www.ncbi.nlm.nih.gov/snp/rs759106494/) |
| Variant type | single nucleotide variant |
| Location | chr17:3498953-3498953 (GRCh38) |
| ClinVar | [VCV322667](https://www.ncbi.nlm.nih.gov/clinvar/variation/322667/) |

**All HGVS expressions:** `NC_000017.10:g.3402247G>A`, `NC_000017.11:g.3498953G>A`, `NG_008399.2:g.30308G>A`, `NG_008399.3:g.29845G>A`, `NM_000049.4:c.807G>A`, `NM_001128085.1:c.807G>A`, `NM_001321336.2:c.-74+14459C>T`, `NM_001321337.2:c.-74+14459C>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 (below), not from a missing predictor score.
- Conservation: phyloP -1.326, GERP -3.01 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.395**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0061%** (nfe) · FAF95 0.00495% · FAF99 0.00455% · 72/1,179,424 in the highest group · 80/1,612,982 alleles overall — very rare (popmax 0.0061%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0061% | 16,381 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,801 |
| African / African-American | 0.00267% | 37,427 |
| South Asian | 0.0022% | 45,447 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,026 |

*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 **269** lies in a β-strand.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-02-02.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-07 |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2019-05-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-02 |

## 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.Thr269Met](/variant/aspa-p-thr269met), [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), [ASPA c.527-2A>G](/variant/aspa-c-527-minus-2a-g), [ASPA c.634+1G>T](/variant/aspa-c-634-plus-1g-t).

### 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 322667). 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.*