Is ARSA p.Leu433= (c.1299G>A) pathogenic?

ARSA p.Leu433= (c.1299G>A) is classified Likely benign in ARSA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-29). Very rare (popmax 8.51e-05%, nfe); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Leu433= (c.1299G>A)?

ARSA p.Leu433= (c.1299G>A) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Leu433= (c.1299G>A) in the general population?

ARSA p.Leu433= (c.1299G>A) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Leu433=

c.1299G>A · rs1433733179 · VCV1960362

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.1	GERP -4.7
Overall
CADD	3.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,175,394 alleles

Overall 0.000657% 1/152,258 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.Leu433=
Coding: c.1299G>A
MANE Select: NM_000487
dbSNP: rs1433733179
Type: single nucleotide variant
Location: chr22:50625376 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 433: a turn

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.Leu433Arg Uncertain significance ★ same residue
ARSA p.Leu433Val Conflicting classifications of pathogenicity ★ 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-leu433 (accessed [today's date]).

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