Is ARSA p.Arg202His (c.605G>A) pathogenic?

ARSA p.Arg202His (c.605G>A) is classified Conflicting classifications of pathogenicity in ARSA (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-03-03). Ultra-rare (popmax 0.0825%, mid); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Arg202His (c.605G>A)?

ARSA p.Arg202His (c.605G>A) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Arg202His (c.605G>A) in the general population?

ARSA p.Arg202His (c.605G>A) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Arg202His

c.605G>A · rs201794808 · VCV1430325

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.431	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP 1.1, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	16.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.0129% 208/1,613,232 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
Admixed American	0.0666%	1,501
East Asian	0.0535%	1,870
Remaining individualsnot grpmax-eligible	0.0256%	3,905
African / African-American	0.0173%	5,773
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
European (non-Finnish)	0.00898%	11,131
South Asian	0.0011%	91,068

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.Arg202His
Coding: c.605G>A
MANE Select: NM_000487
dbSNP: rs201794808
Type: single nucleotide variant
Location: chr22:50626913 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 202: an α-helix

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.Arg202Cys 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
ARSA c.224+1G>A Likely pathogenic ★★ same condition
ARSA c.225-1G>C 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-arg202his (accessed [today's date]).

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