Is ARSA p.Ser334= (c.1002C>T) pathogenic?

ARSA p.Ser334= (c.1002C>T) is classified Benign/Likely benign in ARSA (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-31). Low-frequency (popmax 2%, sas); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Ser334= (c.1002C>T)?

ARSA p.Ser334= (c.1002C>T) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Ser334= (c.1002C>T) in the general population?

ARSA p.Ser334= (c.1002C>T) is low-frequency (popmax 2%, sas) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Ser334=

c.1002C>T · rs147027229 · VCV280986

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2%, 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 4.1	GERP -1.2, phastCons 1
Overall
CADD	9.019	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2% South Asian · 1,746/87,126 alleles

Filtering AF 1.93% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.89%

Overall 0.456% 7,258/1,589,948 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2%	50
Finnishnot grpmax-eligible	1.54%	65
Middle Eastern	0.895%	112
Remaining individualsnot grpmax-eligible	0.459%	218
Ashkenazi Jewishnot grpmax-eligible	0.4%	250
European (non-Finnish)	0.335%	298
Admixed American	0.266%	375
African / African-American	0.056%	1,785

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.Ser334=
Coding: c.1002C>T
MANE Select: NM_000487
dbSNP: rs147027229
Type: single nucleotide variant
Location: chr22:50626041 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 334: 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 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
ARSA c.225-2A>G 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-ser334 (accessed [today's date]).

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