Is ASPA p.Ile308fs (c.922del) pathogenic?

ASPA p.Ile308fs (c.922del) is classified Likely pathogenic in ASPA (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-18). Very rare (popmax 8.47e-05%, nfe); Associated with Canavan disease.

What condition is associated with ASPA p.Ile308fs (c.922del)?

ASPA p.Ile308fs (c.922del) is associated with Canavan disease (ClinVar).

How common is ASPA p.Ile308fs (c.922del) in the general population?

ASPA p.Ile308fs (c.922del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Canavan disease inherited?

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

ASPA p.Ile308fs

c.922del · rs1057516309 · VCV370201

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-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 -0.1	GERP -2.8, phastCons 0.052

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,976 alleles

Overall 0.000137% 2/1,461,774 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)grpmax	8.47e-05%	1,179,976

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Ile308fs
Coding: c.922del
MANE Select: NM_000049
dbSNP: rs1057516309
Type: Deletion
Location: chr17:3499068 (GRCh38)
Gene constraint: LOEUF 1.098 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.14 · 8 PDB

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.Ile308Val Uncertain significance ★★ ⚠ same residue
ASPA p.Ile308= Likely benign ★ 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

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-ile308fs (accessed [today's date]).

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