Is ARSA p.Pro6Leu (c.17C>T) pathogenic?

ARSA p.Pro6Leu (c.17C>T) is classified Uncertain significance in ARSA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-04). Absent from gnomAD v4.1; Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Pro6Leu (c.17C>T)?

ARSA p.Pro6Leu (c.17C>T) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Pro6Leu (c.17C>T) in the general population?

ARSA p.Pro6Leu (c.17C>T) is absent from gnomAD v4.1 (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Pro6Leu

c.17C>T · rs2518337632 · VCV1953415

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.174	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2.1, phastCons 0.003
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	0.677	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARSA
Protein: p.Pro6Leu
Coding: c.17C>T
MANE Select: NM_000487
dbSNP: rs2518337632
Type: single nucleotide variant
Location: chr22:50627763 (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.Pro6= 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-pro6leu (accessed [today's date]).

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