Is ARSA p.Pro428Leu (c.1283C>T) pathogenic?

ARSA p.Pro428Leu (c.1283C>T) is classified Pathogenic in ARSA (ClinVar, Multiple submitters, 34 submitters; last evaluated 2026-09-17). Ultra-rare (popmax 0.0536%, nfe); Associated with Fetal anomalies with a likely genetic cause.

What condition is associated with ARSA p.Pro428Leu (c.1283C>T)?

ARSA p.Pro428Leu (c.1283C>T) is associated with Fetal anomalies with a likely genetic cause, intellectual disability, metachromatic leukodystrophy, juvenile form (ClinVar).

How common is ARSA p.Pro428Leu (c.1283C>T) in the general population?

ARSA p.Pro428Leu (c.1283C>T) is ultra-rare (popmax 0.0536%, nfe) (gnomAD).

ARSA p.Pro428Leu

c.1283C>T · rs28940893 · VCV3052

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 34 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0536%, nfe)

Conditions

Fetal anomalies with a likely genetic cause

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.848	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0536% European (non-Finnish) · 627/1,170,744 alleles

Filtering AF 0.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0487%

Overall 0.0448% 716/1,599,780 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0781%	1,280
European (non-Finnish)grpmax	0.0536%	1,867
Remaining individualsnot grpmax-eligible	0.0324%	3,089
African / African-American	0.0121%	8,296
Admixed American	0.0118%	8,483
South Asian	0.00333%	30,020
East Asian	0.00224%	44,622

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro428Leu
Coding: c.1283C>T
MANE Select: NM_000487
dbSNP: rs28940893
Type: single nucleotide variant
Location: chr22:50625392 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 428: a UniProt-annotated variant site (in mld; late-infantile form); a β-strand

Full ARSA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fetal anomalies with a likely genetic cause

Also linked: intellectual disability metachromatic leukodystrophy, juvenile form metachromatic leukodystrophy, adult form metachromatic leukodystrophy

Similar variants

ARSA p.Pro428Ala Likely pathogenic ★ same residue
ARSA p.Pro428Ser Likely pathogenic ★ same residue
ARSA p.Pro428= Likely benign ★ same residue
ARSA p.Pro428Arg 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
ARSA c.1108-3C>G Pathogenic/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-pro428leu (accessed [today's date]).

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