Is ASPA p.His244Arg (c.731A>G) pathogenic?

ASPA p.His244Arg (c.731A>G) is classified Likely pathogenic in ASPA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-30). AlphaMissense: likely pathogenic (0.83); Very rare (popmax 0.000598%, nfe); Associated with Canavan Disease, Familial Form.

What condition is associated with ASPA p.His244Arg (c.731A>G)?

ASPA p.His244Arg (c.731A>G) is associated with Canavan Disease, Familial Form, Canavan disease (ClinVar).

How common is ASPA p.His244Arg (c.731A>G) in the general population?

ASPA p.His244Arg (c.731A>G) is very rare (popmax 0.000598%, nfe) (gnomAD).

What do computational predictors say about ASPA p.His244Arg (c.731A>G)?

AlphaMissense predicts likely pathogenic (score 0.83) — an in-silico prediction, not a clinical call.

ASPA p.His244Arg

c.731A>G · rs1057516995 · VCV371086

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.83 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000598%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Canavan Disease, Familial Form

Computational evidence

Protein change
AlphaMissense	0.83	likely pathogenic ✓ concordant with ClinVar
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -15.86	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	25.7	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 0.000598% European (non-Finnish) · 7/1,170,866 alleles

Filtering AF 0.000249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000482% 7/1,451,812 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.His244Arg
Coding: c.731A>G
MANE Select: NM_000049
dbSNP: rs1057516995
Type: single nucleotide variant
Location: chr17:3494446 (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 244: 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, Familial Form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Canavan disease

Similar variants

ASPA p.His244Pro Uncertain significance ★★ ⚠ same residue
ASPA p.His244Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ASPA p.His244= 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

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-his244arg (accessed [today's date]).

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