Is ASPA p.Arg168His (c.503G>A) pathogenic?

ASPA p.Arg168His (c.503G>A) is classified Pathogenic/Likely pathogenic in ASPA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-31). AlphaMissense: likely pathogenic (0.599); Very rare (popmax 0.00373%, nfe); Associated with Canavan disease.

What condition is associated with ASPA p.Arg168His (c.503G>A)?

ASPA p.Arg168His (c.503G>A) is associated with Canavan disease (ClinVar).

How common is ASPA p.Arg168His (c.503G>A) in the general population?

ASPA p.Arg168His (c.503G>A) is very rare (popmax 0.00373%, 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.Arg168His (c.503G>A)?

AlphaMissense predicts likely pathogenic (score 0.599) — an in-silico prediction, not a clinical call.

ASPA p.Arg168His

c.503G>A · rs770706390 · VCV550697

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.599 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Canavan disease

Computational evidence

Protein change
AlphaMissense	0.599	likely pathogenic ✓ concordant with ClinVar
REVEL	0.754	pathogenic-leaning
SaProt	LLR -7.36	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	23.2	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 0.00373% European (non-Finnish) · 44/1,179,746 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00328% 53/1,613,668 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,826
European (non-Finnish)grpmax	0.00373%	26,812
Admixed American	0.00333%	29,996
South Asian	0.0022%	45,536
Finnishnot grpmax-eligible	0.00156%	64,000
African / African-American	0.00134%	74,890

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg168His
Coding: c.503G>A
MANE Select: NM_001170698 · reported on NM_000049
dbSNP: rs770706390
Type: single nucleotide variant
Location: chr17:3483569 (GRCh38)

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

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-arg168his (accessed [today's date]).

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