Is ASPA p.Asp249Val (c.746A>T) pathogenic?

ASPA p.Asp249Val (c.746A>T) is classified Pathogenic/Likely pathogenic in ASPA (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-15). AlphaMissense: likely pathogenic (0.831); Very rare (popmax 0.00181%, nfe); Associated with ASPA-related disorder.

What condition is associated with ASPA p.Asp249Val (c.746A>T)?

ASPA p.Asp249Val (c.746A>T) is associated with ASPA-related disorder, Canavan disease (ClinVar).

How common is ASPA p.Asp249Val (c.746A>T) in the general population?

ASPA p.Asp249Val (c.746A>T) is very rare (popmax 0.00181%, nfe) (gnomAD).

What do computational predictors say about ASPA p.Asp249Val (c.746A>T)?

AlphaMissense predicts likely pathogenic (score 0.831) — an in-silico prediction, not a clinical call.

ASPA p.Asp249Val

c.746A>T · rs104894552 · VCV2615

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00181%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ASPA-related disorder

Computational evidence

Protein change
AlphaMissense	0.831	likely pathogenic ✓ concordant with ClinVar
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -13.48	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	32.0	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 0.00181% European (non-Finnish) · 21/1,162,938 alleles

Filtering AF 0.00116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000985%

Overall 0.00184% 29/1,576,364 alleles · very rare exomes 29/1,424,098 · genomes 0/152,266 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00988%	10,125
Finnishnot grpmax-eligible	0.00316%	31,596
European (non-Finnish)grpmax	0.00181%	55,378

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.Asp249Val
Coding: c.746A>T
MANE Select: NM_000049
dbSNP: rs104894552
Type: single nucleotide variant
Location: chr17:3498892 (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 249: a UniProt-annotated variant site (in cand); a turn

Full ASPA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ASPA-related disorder

Also linked: Canavan disease

Similar variants

ASPA p.Asp249Asn 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-asp249val (accessed [today's date]).

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