Is ARSA p.Leu336= (c.1006C>T) pathogenic?

ARSA p.Leu336= (c.1006C>T) is classified Likely benign in ARSA (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-20). Ultra-rare (popmax 0.0218%, sas); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Leu336= (c.1006C>T)?

ARSA p.Leu336= (c.1006C>T) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Leu336= (c.1006C>T) in the general population?

ARSA p.Leu336= (c.1006C>T) is ultra-rare (popmax 0.0218%, sas) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Leu336=

c.1006C>T · rs778950224 · VCV762832

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, sas)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -1.2, phastCons 1
Overall
CADD	6.155	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0218% South Asian · 19/87,076 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00139% 20/1,436,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0218%	4,583
East Asian	0.00227%	44,028

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.Leu336=
Coding: c.1006C>T
MANE Select: NM_000487
dbSNP: rs778950224
Type: single nucleotide variant
Location: chr22:50626037 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 336: 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.Leu336Pro Conflicting classifications of pathogenicity ★ same residue
ARSA p.Leu336Val Uncertain significance ★ 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

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-leu336 (accessed [today's date]).

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