Is ARSA p.Arg99fs (c.295dup) pathogenic?

ARSA p.Arg99fs (c.295dup) is classified Pathogenic in ARSA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-22). Very rare (popmax 0.000171%, nfe); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Arg99fs (c.295dup)?

ARSA p.Arg99fs (c.295dup) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Arg99fs (c.295dup) in the general population?

ARSA p.Arg99fs (c.295dup) is very rare (popmax 0.000171%, nfe) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Arg99fs

c.295dup · rs1555901056 · VCV554584

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

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 2 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.96	GERP -4

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000171% European (non-Finnish) · 2/1,171,038 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000139% 2/1,440,496 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: ARSA
Protein: p.Arg99fs
Coding: c.295dup
MANE Select: NM_000487
dbSNP: rs1555901056
Type: Duplication
Location: chr22:50627335 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 99: a UniProt-annotated variant site (in mld; adult type); a UniProt-annotated variant site (in mld; late-infantile form)

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.Arg99Gln Uncertain significance ★★ same residue
ARSA p.Arg99Leu Uncertain significance ★ same residue
ARSA p.Arg99Pro Conflicting classifications of pathogenicity ★ same residue
ARSA p.Arg99Trp Uncertain significance ★ same residue
ARSA p.Arg99= Likely benign ★ same residue
ARSA p.Arg498fs Pathogenic/Likely pathogenic ★★ same condition
ARSA p.Gly449fs Pathogenic ★★ same condition
ARSA p.Gly81fs 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-arg99fs (accessed [today's date]).

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