Is ARSA p.Ser297= (c.891C>T) pathogenic?

ARSA p.Ser297= (c.891C>T) is classified Conflicting classifications of pathogenicity in ARSA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-03). Ultra-rare (popmax 0.0385%, sas); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Ser297= (c.891C>T)?

ARSA p.Ser297= (c.891C>T) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Ser297= (c.891C>T) in the general population?

ARSA p.Ser297= (c.891C>T) is ultra-rare (popmax 0.0385%, sas) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Ser297=

c.891C>T · rs770536697 · VCV1155946

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, sas)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -3.2
Overall
CADD	5.293	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0385% South Asian · 35/91,002 alleles

Filtering AF 0.0283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00514% 83/1,613,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0385%	2,600
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,823
East Asian	0.00446%	22,439
European (non-Finnish)	0.00347%	28,779
African / African-American	0.00133%	74,930

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.Ser297=
Coding: c.891C>T
MANE Select: NM_000487
dbSNP: rs770536697
Type: single nucleotide variant
Location: chr22:50626242 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB

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.Ser297Tyr Pathogenic ★ same residue
ARSA p.Ser297Ala Uncertain significance same residue
ARSA p.Ser297Cys 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

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-ser297 (accessed [today's date]).

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