Is ASPA p.Val186Asp (c.557T>A) pathogenic?

ASPA p.Val186Asp (c.557T>A) is classified Pathogenic in ASPA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-23). AlphaMissense: likely pathogenic (0.9519); Very rare (popmax 8.48e-05%, nfe); Associated with Canavan disease.

What condition is associated with ASPA p.Val186Asp (c.557T>A)?

ASPA p.Val186Asp (c.557T>A) is associated with Canavan disease (ClinVar).

How common is ASPA p.Val186Asp (c.557T>A) in the general population?

ASPA p.Val186Asp (c.557T>A) 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.Val186Asp (c.557T>A)?

AlphaMissense predicts likely pathogenic (score 0.9519) — an in-silico prediction, not a clinical call.

ASPA p.Val186Asp

c.557T>A · rs747438350 · VCV2137874

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9519 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Canavan disease

Computational evidence

Protein change
AlphaMissense	0.9519	likely pathogenic ✓ concordant with ClinVar · top 8% in ASPA
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -14.51	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	29.6	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) · 1/1,179,682 alleles

Overall 0.000657% 1/152,150 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.Val186Asp
Coding: c.557T>A
MANE Select: NM_000049
dbSNP: rs747438350
Type: single nucleotide variant
Location: chr17:3489265 (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 186: 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.Val186Phe Pathogenic/Likely pathogenic ★★ same residue
ASPA p.Val186Ala 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-val186asp (accessed [today's date]).

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