Is ARSB p.Leu321Pro (c.962T>C) pathogenic?

ARSB p.Leu321Pro (c.962T>C) is classified Pathogenic in ARSB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.7687); Very rare (popmax 6.84e-05%); Associated with mucopolysaccharidosis type 6.

What condition is associated with ARSB p.Leu321Pro (c.962T>C)?

ARSB p.Leu321Pro (c.962T>C) is associated with mucopolysaccharidosis type 6 (ClinVar).

How common is ARSB p.Leu321Pro (c.962T>C) in the general population?

ARSB p.Leu321Pro (c.962T>C) is very rare (popmax 6.84e-05%) (gnomAD).

How is Mucopolysaccharidosis type 6 inherited?

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

What do computational predictors say about ARSB p.Leu321Pro (c.962T>C)?

AlphaMissense predicts likely pathogenic (score 0.7687) — an in-silico prediction, not a clinical call.

ARSB p.Leu321Pro

c.962T>C · rs1554079320 · VCV559830

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 6

Computational evidence

Protein change
AlphaMissense	0.7687	likely pathogenic ✓ concordant with ClinVar
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -10.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,892 alleles · very rare

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: ARSB
Protein: p.Leu321Pro
Coding: c.962T>C
MANE Select: NM_020427 · reported on NM_000046
dbSNP: rs1554079320
Type: single nucleotide variant
Location: chr5:78885764 (GRCh38)
Structure: AlphaFold pLDDT 84.32 · 2 PDB

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

Disease context

mucopolysaccharidosis type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mucopolysaccharidosis type 6 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ARSB p.Leu321Gln Likely pathogenic ★ same residue
ARSB p.Leu321= Likely benign ★ same residue
ARSB p.Leu321Arg Uncertain significance ★ ⚠ same residue
ARSB c.1142+1G>A Pathogenic ★★ same condition
ARSB c.1142+1G>T Pathogenic ★★ same condition
ARSB c.1142+2T>A Pathogenic/Likely pathogenic ★★ same condition
ARSB c.1142+2T>C Pathogenic ★★ same condition
ARSB c.1143-1G>A 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/arsb-p-leu321pro (accessed [today's date]).

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