Is ASPA p.Ala57Val (c.170C>T) pathogenic?

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.

What condition is associated with ASPA p.Ala57Val (c.170C>T)?

ASPA p.Ala57Val (c.170C>T) is associated with Canavan disease (ClinVar).

How common is ASPA p.Ala57Val (c.170C>T) in the general population?

ASPA p.Ala57Val (c.170C>T) is absent from gnomAD v4.1 (gnomAD).

How is Canavan disease inherited?

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

What do computational predictors say about ASPA p.Ala57Val (c.170C>T)?

AlphaMissense predicts likely pathogenic (score 0.944) — an in-silico prediction, not a clinical call.

ASPA p.Ala57Val

c.170C>T · rs1555538148 · VCV556428

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Canavan disease

Computational evidence

Protein change
AlphaMissense	0.944	likely pathogenic ✓ concordant with ClinVar · top 10% in ASPA
REVEL	0.973	strongly pathogenic-leaning
SaProt	LLR -12.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ASPA
Protein: p.Ala57Val
Coding: c.170C>T
MANE Select: NM_000049
dbSNP: rs1555538148
Type: single nucleotide variant
Location: chr17:3476329 (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 57: a UniProt-annotated variant site (in cand); a UniProt-annotated variant site (in cand; <1% residual enzyme activity); an α-helix

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.Ala57Thr Pathogenic/Likely pathogenic ★★ same residue
ASPA p.Ala57Ser Likely pathogenic ★ ⚠ same residue
ASPA p.Ala57= Likely benign ★ same residue
ASPA c.236+2T>C Likely pathogenic ★★ same condition
ASPA c.237-1G>T Likely pathogenic ★★ same condition
ASPA c.237-2A>T Pathogenic/Likely pathogenic ★★ same condition
ASPA c.527-1G>A Likely pathogenic ★★ same condition
ASPA c.527-2A>C 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-ala57val (accessed [today's date]).

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