Is ARSA p.Pro349fs (c.1046del) pathogenic?

ARSA p.Pro349fs (c.1046del) is classified Pathogenic in ARSA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-07). Absent from gnomAD; Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Pro349fs (c.1046del)?

ARSA p.Pro349fs (c.1046del) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Pro349fs (c.1046del) in the general population?

ARSA p.Pro349fs (c.1046del) is absent from gnomAD (gnomAD).

How is Metachromatic leukodystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ARSA p.Pro349fs

c.1046del · rs1603444908 · VCV661357

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -8.8	GERP -4.3

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ARSA
Protein: p.Pro349fs
Coding: c.1046del
MANE Select: NM_000487
dbSNP: rs1603444908
Type: Deletion
Location: chr22:50625997 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 349: an α-helix; a disulfide bond

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

Disease context

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

For Metachromatic leukodystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ARSA p.Pro349= Likely benign ★ same residue
ARSA c.979_979+3del Pathogenic/Likely pathogenic ★★ same condition
ARSA p.Ala12fs Pathogenic ★★ same condition
ARSA p.Ala5fs Pathogenic ★★ same condition
ARSA p.Arg21fs Pathogenic/Likely pathogenic ★★ same condition
ARSA p.Arg82fs Pathogenic/Likely pathogenic ★★ same condition
ARSA p.Asp37fs Pathogenic ★★ same condition
ARSA p.Gly101fs 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/arsa-p-pro349fs (accessed [today's date]).

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