Is ASPA p.Ala165Thr (c.493G>A) pathogenic?

ASPA p.Ala165Thr (c.493G>A) is classified Uncertain significance in ASPA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely benign (0.1932); Very rare (popmax 0.000339%, nfe); Associated with Canavan disease.

What condition is associated with ASPA p.Ala165Thr (c.493G>A)?

ASPA p.Ala165Thr (c.493G>A) is associated with Canavan disease (ClinVar).

How common is ASPA p.Ala165Thr (c.493G>A) in the general population?

ASPA p.Ala165Thr (c.493G>A) is very rare (popmax 0.000339%, 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.Ala165Thr (c.493G>A)?

AlphaMissense predicts likely benign (score 0.1932) — an in-silico prediction, not a clinical call.

ASPA p.Ala165Thr

c.493G>A · rs2150748669 · VCV1419733

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Canavan disease

Computational evidence

Protein change
AlphaMissense	0.1932	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -3.88	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 3.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	16.85	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

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,972 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,820 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.Ala165Thr
Coding: c.493G>A
MANE Select: NM_000049
dbSNP: rs2150748669
Type: single nucleotide variant
Location: chr17:3483559 (GRCh38)
Gene constraint: LOEUF 1.098 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.14 · 8 PDB

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.Ala165Val Uncertain significance ★ ⚠ 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
ASPA c.634+1G>T 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-ala165thr (accessed [today's date]).

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