Is ARSA p.Pro379Leu (c.1136C>T) pathogenic?

ARSA p.Pro379Leu (c.1136C>T) is classified Pathogenic in ARSA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-09-17). Ultra-rare (popmax 0.033%, mid); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Pro379Leu (c.1136C>T)?

ARSA p.Pro379Leu (c.1136C>T) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Pro379Leu (c.1136C>T) in the general population?

ARSA p.Pro379Leu (c.1136C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Pro379Leu

c.1136C>T · rs74315478 · VCV3083

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.627	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.0013% 19/1,461,436 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.0048%	20,835
African / African-American	0.00133%	75,048
European (non-Finnish)	0.0011%	90,767

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.Pro379Leu
Coding: c.1136C>T
MANE Select: NM_000487
dbSNP: rs74315478
Type: single nucleotide variant
Location: chr22:50625653 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 379: 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.Pro379= Likely benign ★★ same residue
ARSA p.Pro379Gln Likely pathogenic ★ same residue
ARSA p.Pro379fs Pathogenic ★ same residue
ARSA p.Pro379Arg 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

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-pro379leu (accessed [today's date]).

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