Is ARSA p.Arg99Pro (c.296G>C) pathogenic?

ARSA p.Arg99Pro (c.296G>C) is classified Conflicting classifications of pathogenicity in ARSA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-30). Ultra-rare (popmax 0.0176%, amr); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Arg99Pro (c.296G>C)?

ARSA p.Arg99Pro (c.296G>C) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Arg99Pro (c.296G>C) in the general population?

ARSA p.Arg99Pro (c.296G>C) is ultra-rare (popmax 0.0176%, amr) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Arg99Pro

c.296G>C · rs759295985 · VCV965478

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, amr)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.465	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.96	GERP -4
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	14.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% Admixed American · 10/56,658 alleles

Filtering AF 0.00949% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00727%

Overall 0.00283% 45/1,592,644 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0176%	5,666
Middle Eastern	0.0165%	6,054
European (non-Finnish)	0.00282%	35,486
Remaining individualsnot grpmax-eligible	0.00162%	61,672

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.Arg99Pro
Coding: c.296G>C
MANE Select: NM_000487
dbSNP: rs759295985
Type: single nucleotide variant
Location: chr22:50627335 (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.Arg99Trp Uncertain significance ★ 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-arg99pro (accessed [today's date]).

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