Is ARSA p.Arg301Trp (c.901C>T) pathogenic?

ARSA p.Arg301Trp (c.901C>T) is classified Conflicting classifications of pathogenicity in ARSA (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-09-17). Very rare (popmax 0.0011%, sas); Associated with ARSA-related disorder.

What condition is associated with ARSA p.Arg301Trp (c.901C>T)?

ARSA p.Arg301Trp (c.901C>T) is associated with ARSA-related disorder, metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Arg301Trp (c.901C>T) in the general population?

ARSA p.Arg301Trp (c.901C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

ARSA p.Arg301Trp

c.901C>T · rs794727704 · VCV1048519

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

ARSA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.794	moderately pathogenic-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.5	GERP -1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,970 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000479% 7/1,461,042 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,630
South Asiangrpmax	0.0011%	90,970
European (non-Finnish)	0.000424%	235,975

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg301Trp
Coding: c.901C>T
MANE Select: NM_000487
dbSNP: rs794727704
Type: single nucleotide variant
Location: chr22:50626232 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 301: a disulfide bond

Full ARSA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ARSA-related disorder

Also linked: metachromatic leukodystrophy

Similar variants

ARSA p.Arg301Gln Uncertain significance ★★ same residue
ARSA p.Arg301Leu Likely pathogenic ★ same residue
ARSA p.Arg301Gly Conflicting classifications of pathogenicity ★ same residue
ARSA p.Arg301Pro 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

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-arg301trp (accessed [today's date]).

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