Is ASPA p.Pro183Leu (c.548C>T) pathogenic?

ASPA p.Pro183Leu (c.548C>T) is classified Likely pathogenic in ASPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-01). AlphaMissense: ambiguous (0.5455); Very rare (popmax 8.48e-05%, nfe); Associated with Canavan disease.

What condition is associated with ASPA p.Pro183Leu (c.548C>T)?

ASPA p.Pro183Leu (c.548C>T) is associated with Canavan disease (ClinVar).

How common is ASPA p.Pro183Leu (c.548C>T) in the general population?

ASPA p.Pro183Leu (c.548C>T) is very rare (popmax 8.48e-05%, nfe) (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.Pro183Leu (c.548C>T)?

AlphaMissense predicts ambiguous (score 0.5455) — an in-silico prediction, not a clinical call.

ASPA p.Pro183Leu

c.548C>T · rs1555539857 · VCV1705409

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5455 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Canavan disease

Computational evidence

Protein change
AlphaMissense	0.5455	ambiguous
REVEL	0.871	moderately pathogenic-leaning
SaProt	LLR -12.72	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	28.7	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,436 alleles

Overall 6.85e-05% 1/1,460,272 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.Pro183Leu
Coding: c.548C>T
MANE Select: NM_000049
dbSNP: rs1555539857
Type: single nucleotide variant
Location: chr17:3489256 (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 183: a UniProt-annotated variant site (in cand)

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.Pro183His Pathogenic/Likely pathogenic ★★ same residue
ASPA p.Pro183Ser Likely pathogenic ★ 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
ASPA c.527-2A>G 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-pro183leu (accessed [today's date]).

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