Is ASPA p.Leu30Pro (c.89T>C) pathogenic?

ASPA p.Leu30Pro (c.89T>C) is classified Likely pathogenic in ASPA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-27). AlphaMissense: likely pathogenic (0.9792); Absent from gnomAD v4.1; Associated with Canavan Disease, Familial Form.

What condition is associated with ASPA p.Leu30Pro (c.89T>C)?

ASPA p.Leu30Pro (c.89T>C) is associated with Canavan Disease, Familial Form, Canavan disease (ClinVar).

How common is ASPA p.Leu30Pro (c.89T>C) in the general population?

ASPA p.Leu30Pro (c.89T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ASPA p.Leu30Pro (c.89T>C)?

AlphaMissense predicts likely pathogenic (score 0.9792) — an in-silico prediction, not a clinical call.

ASPA p.Leu30Pro

c.89T>C · rs1555538144 · VCV556181

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9792 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Canavan Disease, Familial Form

Computational evidence

Protein change
AlphaMissense	0.9792	likely pathogenic ✓ concordant with ClinVar · top 3% in ASPA
REVEL	0.994	strongly pathogenic-leaning
SaProt	LLR -12.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	32.0	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.Leu30Pro
Coding: c.89T>C
MANE Select: NM_000049
dbSNP: rs1555538144
Type: single nucleotide variant
Location: chr17:3476248 (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 30: 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, Familial Form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Canavan disease

Similar variants

ASPA p.Leu30Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ASPA p.Leu30= 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-leu30pro (accessed [today's date]).

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