Is ASPA p.Met261fs (c.781_782del) pathogenic?

ASPA p.Met261fs (c.781782del) is classified Likely pathogenic in ASPA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). Very rare (popmax 8.5e-05%, nfe); Associated with Canavan disease.

What condition is associated with ASPA p.Met261fs (c.781_782del)?

ASPA p.Met261fs (c.781_782del) is associated with Canavan disease (ClinVar).

How common is ASPA p.Met261fs (c.781_782del) in the general population?

ASPA p.Met261fs (c.781_782del) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

How is Canavan disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ASPA p.Met261fs

c.781_782del · VCV4818504

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Conditions

Canavan disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.5	GERP -3.7
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,175,968 alleles

Overall 0.000657% 1/152,108 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ASPA
Protein: p.Met261fs
Coding: c.781_782del
MANE Select: NM_000049
Type: Deletion
Location: chr17:3498927 (GRCh38)
Gene constraint: LOEUF 1.098 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.14 · 8 PDB
Residue 261: a β-strand

Full ASPA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Canavan disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Canavan disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ASPA p.Met261Val Uncertain significance ⚠ same residue
ASPA p.Asp204fs Pathogenic/Likely pathogenic ★★ same condition
ASPA p.Cys152fs Pathogenic/Likely pathogenic ★★ same condition
ASPA p.Cys276fs Pathogenic/Likely pathogenic ★★ same condition
ASPA p.Gln12fs Pathogenic ★★ same condition
ASPA p.Glu129fs Pathogenic ★★ same condition
ASPA p.Ile11fs Pathogenic/Likely pathogenic ★★ same condition
ASPA p.Lys103fs Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aspa-p-met261fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown