Is ARSA p.Ala5fs (c.13del) pathogenic?

ARSA p.Ala5fs (c.13del) is classified Pathogenic in ARSA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-04). Very rare (popmax 0.000262%, nfe); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Ala5fs (c.13del)?

ARSA p.Ala5fs (c.13del) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Ala5fs (c.13del) in the general population?

ARSA p.Ala5fs (c.13del) is very rare (popmax 0.000262%, nfe) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Ala5fs

c.13del · rs919125796 · VCV1460113

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000262%, 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 1 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP -2.9
Overall
CADD	16.54	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000262% European (non-Finnish) · 3/1,146,958 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000259% 4/1,546,196 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0018%	55,600
European (non-Finnish)grpmax	0.000262%	382,320

Finnish 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.Ala5fs
Coding: c.13del
MANE Select: NM_000487
dbSNP: rs919125796
Type: Deletion
Location: chr22:50627767 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB

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.Ala5Val Uncertain significance ★★ same residue
ARSA p.Ala5Thr Uncertain significance ★ same residue
ARSA c.979_979+3del Pathogenic/Likely pathogenic ★★ same condition
ARSA p.Ala12fs 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-ala5fs (accessed [today's date]).

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