Is ARSA p.Ser408Gly (c.1222A>G) pathogenic?

ARSA p.Ser408Gly (c.1222A>G) is classified Likely pathogenic in ARSA (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-13). Absent from gnomAD v4.1; Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Ser408Gly (c.1222A>G)?

ARSA p.Ser408Gly (c.1222A>G) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Ser408Gly (c.1222A>G) in the general population?

ARSA p.Ser408Gly (c.1222A>G) is absent from gnomAD v4.1 (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Ser408Gly

c.1222A>G · rs199476361 · VCV68118

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,600,986)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.708	pathogenic-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,600,986). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ARSA
Protein: p.Ser408Gly
Coding: c.1222A>G
MANE Select: NM_000487
dbSNP: rs199476361
Type: single nucleotide variant
Location: chr22:50625453 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 408: a UniProt-annotated variant site (in mld; late-infantile-onset); a UniProt-annotated variant site (in mld; adult type); a β-strand; 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.Ser408Arg Likely pathogenic ★ same residue
ARSA p.Ser408Asn Likely pathogenic ★ same residue
ARSA p.Ser408Thr Likely pathogenic ★ same residue
ARSA p.Ser408_Thr410del Pathogenic ★★ same residue
ARSA p.Ser408fs Likely 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-ser408gly (accessed [today's date]).

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