Is ARSA p.Pro166= (c.498G>A) pathogenic?

ARSA p.Pro166= (c.498G>A) is classified Uncertain significance in ARSA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-04). Ultra-rare (popmax 0.0132%, sas); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Pro166= (c.498G>A)?

ARSA p.Pro166= (c.498G>A) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Pro166= (c.498G>A) in the general population?

ARSA p.Pro166= (c.498G>A) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Pro166=

c.498G>A · rs545521822 · VCV2158006

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.94	acceptor gain · deltas
Pangolin	Δ0.65	gain · loss 0.24 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -2.5	GERP -4.3
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/90,992 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.0013% 21/1,609,654 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,583
Remaining individualsnot grpmax-eligible	0.00321%	31,155
East Asian	0.00223%	44,782
Admixed American	0.00167%	59,922
European (non-Finnish)	0.000424%	235,580

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.Pro166=
Coding: c.498G>A
MANE Select: NM_000487
dbSNP: rs545521822
Type: single nucleotide variant
Location: chr22:50627020 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 166: 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 p.Pro166fs Likely pathogenic same residue
ARSA p.Pro166Leu 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

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-pro166 (accessed [today's date]).

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