Is ARSA p.Ile324= (c.972C>T) pathogenic?

ARSA p.Ile324= (c.972C>T) is classified Benign/Likely benign in ARSA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Rare (popmax 0.247%, amr); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Ile324= (c.972C>T)?

ARSA p.Ile324= (c.972C>T) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Ile324= (c.972C>T) in the general population?

ARSA p.Ile324= (c.972C>T) is rare (popmax 0.247%, amr) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Ile324=

c.972C>T · rs200567315 · VCV703468

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.247%, amr)

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 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.3	GERP -4
Overall
CADD	5.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.247% Admixed American · 142/57,540 alleles

Filtering AF 0.214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.201%

Overall 0.0115% 184/1,603,656 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.247%	405
Remaining individualsnot grpmax-eligible	0.00643%	15,543
African / African-American	0.00533%	18,749
East Asian	0.0045%	22,210
European (non-Finnish)	0.00272%	36,754

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.Ile324=
Coding: c.972C>T
MANE Select: NM_000487
dbSNP: rs200567315
Type: single nucleotide variant
Location: chr22:50626161 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 324: a β-strand; 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.Ile324Phe Pathogenic ★ same residue
ARSA p.Ile324Thr Uncertain significance ★ same residue
ARSA p.Ile324Val 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

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-ile324 (accessed [today's date]).

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