Is ASPA p.Leu75Pro (c.224T>C) pathogenic?

ASPA p.Leu75Pro (c.224T>C) is classified Uncertain significance in ASPA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely benign (0.0483); Absent from gnomAD v4.1; Associated with Canavan disease.

What condition is associated with ASPA p.Leu75Pro (c.224T>C)?

ASPA p.Leu75Pro (c.224T>C) is associated with Canavan disease (ClinVar).

How common is ASPA p.Leu75Pro (c.224T>C) in the general population?

ASPA p.Leu75Pro (c.224T>C) 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.Leu75Pro (c.224T>C)?

AlphaMissense predicts likely benign (score 0.0483) — an in-silico prediction, not a clinical call.

ASPA p.Leu75Pro

c.224T>C · rs2150741914 · VCV1377025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0483 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Canavan disease

Computational evidence

Protein change
AlphaMissense	0.0483	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -2.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -3.7, phastCons 0.14
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	14.35	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Leu75Pro
Coding: c.224T>C
MANE Select: NM_000049
dbSNP: rs2150741914
Type: single nucleotide variant
Location: chr17:3476383 (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 75: 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 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
ASPA c.634+1G>T Pathogenic/Likely pathogenic ★★ same condition
ASPA c.635-1G>C 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-leu75pro (accessed [today's date]).

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