Is ARSA p.Asp337Val (c.1010A>T) pathogenic?

ARSA p.Asp337Val (c.1010A>T) is classified Pathogenic/Likely pathogenic in ARSA (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-20). Very rare (popmax 0.00949%, nfe); Associated with leukodystrophy.

What condition is associated with ARSA p.Asp337Val (c.1010A>T)?

ARSA p.Asp337Val (c.1010A>T) is associated with leukodystrophy, metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Asp337Val (c.1010A>T) in the general population?

ARSA p.Asp337Val (c.1010A>T) is very rare (popmax 0.00949%, nfe) (gnomAD).

ARSA p.Asp337Val

c.1010A>T · rs74315475 · VCV3080

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00949%, nfe)

Conditions

leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.962	strongly pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00949% European (non-Finnish) · 111/1,169,064 alleles

Filtering AF 0.00799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00751%

Overall 0.0075% 119/1,587,406 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00972%	10,289
European (non-Finnish)grpmax	0.00949%	10,532
African / African-American	0.00268%	37,381

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: ARSA
Protein: p.Asp337Val
Coding: c.1010A>T
MANE Select: NM_000487
dbSNP: rs74315475
Type: single nucleotide variant
Location: chr22:50626033 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 337: an α-helix; a disulfide bond

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

Disease context

leukodystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: metachromatic leukodystrophy

Similar variants

ARSA p.Asp337= Likely benign ★ same residue
ARSA c.1107+1G>A Pathogenic/Likely pathogenic ★★ same condition
ARSA c.1107+1G>T Pathogenic ★★ same condition
ARSA c.1108-2A>G Pathogenic ★★ same condition
ARSA c.1108-3C>G Pathogenic/Likely pathogenic ★★ same condition
ARSA c.1210+1G>A Pathogenic ★★ same condition
ARSA c.224+1G>A Likely pathogenic ★★ same condition
ARSA c.225-1G>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/arsa-p-asp337val (accessed [today's date]).

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