Is ASPA p.Pro280Leu (c.839C>T) pathogenic?

ASPA p.Pro280Leu (c.839C>T) is classified Uncertain significance in ASPA (ClinVar, Single submitter, 2 submitters; last evaluated 2024-12-16). AlphaMissense: ambiguous (0.499); Absent from gnomAD v4.1; Associated with Canavan disease.

What condition is associated with ASPA p.Pro280Leu (c.839C>T)?

ASPA p.Pro280Leu (c.839C>T) is associated with Canavan disease (ClinVar).

How common is ASPA p.Pro280Leu (c.839C>T) in the general population?

ASPA p.Pro280Leu (c.839C>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.Pro280Leu (c.839C>T)?

AlphaMissense predicts ambiguous (score 0.499) — an in-silico prediction, not a clinical call.

ASPA p.Pro280Leu

c.839C>T · rs1555541310 · VCV550525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.499 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Canavan disease

Computational evidence

Protein change
AlphaMissense	0.499	ambiguous
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -13.63	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 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	24.9	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.Pro280Leu
Coding: c.839C>T
MANE Select: NM_000049
dbSNP: rs1555541310
Type: single nucleotide variant
Location: chr17:3498985 (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 280: a UniProt-annotated variant site (in cand); 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.Pro280Ser Pathogenic/Likely pathogenic ★★ same residue
ASPA p.Pro280= 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
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-pro280leu (accessed [today's date]).

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