Is ARSA p.Arg99Trp (c.295C>T) pathogenic?

ARSA p.Arg99Trp (c.295C>T) is classified Uncertain significance in ARSA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-28). Very rare (popmax 0.00788%, sas); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Arg99Trp (c.295C>T)?

ARSA p.Arg99Trp (c.295C>T) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Arg99Trp (c.295C>T) in the general population?

ARSA p.Arg99Trp (c.295C>T) is very rare (popmax 0.00788%, sas) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Arg99Trp

c.295C>T · rs1447282658 · VCV2044525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00788%, sas)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.415	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.17, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00788% South Asian · 7/88,848 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00118% 17/1,441,244 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00788%	12,693
East Asian	0.00227%	44,054
Admixed American	0.00176%	56,896
Remaining individualsnot grpmax-eligible	0.00162%	61,706
African / African-American	0.00134%	74,760
European (non-Finnish)	0.000512%	195,231

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.Arg99Trp
Coding: c.295C>T
MANE Select: NM_000487
dbSNP: rs1447282658
Type: single nucleotide variant
Location: chr22:50627336 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 99: a UniProt-annotated variant site (in mld; adult type); a UniProt-annotated variant site (in mld; late-infantile form)

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.Arg99Gln Uncertain significance ★★ same residue
ARSA p.Arg99Leu Uncertain significance ★ same residue
ARSA p.Arg99Pro Conflicting classifications of pathogenicity ★ same residue
ARSA p.Arg99= Likely benign ★ same residue
ARSA p.Arg99fs Pathogenic ★★ 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

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-arg99trp (accessed [today's date]).

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