Is ARSA p.Asp37fs (c.109_116del) pathogenic?

ARSA p.Asp37fs (c.109116del) is classified Pathogenic in ARSA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-17). Very rare (popmax 0.000608%, nfe); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Asp37fs (c.109_116del)?

ARSA p.Asp37fs (c.109_116del) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Asp37fs (c.109_116del) in the general population?

ARSA p.Asp37fs (c.109_116del) is very rare (popmax 0.000608%, nfe) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Asp37fs

c.109_116del · rs753415648 · VCV555003

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000608%, 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 0.18	GERP -4, phastCons 0.003
Overall
CADD	34.0	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 0.000608% European (non-Finnish) · 7/1,151,076 alleles

Filtering AF 0.000253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000449% 7/1,558,772 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.Asp37fs
Coding: c.109_116del
MANE Select: NM_000487
dbSNP: rs753415648
Type: Deletion
Location: chr22:50627664 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 37: an α-helix

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.Asp37His Pathogenic/Likely pathogenic ★★ same residue
ARSA p.Asp37delinsGluLeuGlyCysTyrGlyHis Pathogenic ★ same residue
ARSA p.Asp37_Gly42dup Uncertain significance 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

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-asp37fs (accessed [today's date]).

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