Is ARSB p.Leu82Pro (c.245T>C) pathogenic?

ARSB p.Leu82Pro (c.245T>C) is classified Pathogenic/Likely pathogenic in ARSB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-24). AlphaMissense: likely pathogenic (0.9042); Very rare (popmax 0.00143%, afr); Associated with mucopolysaccharidosis type 6.

What condition is associated with ARSB p.Leu82Pro (c.245T>C)?

ARSB p.Leu82Pro (c.245T>C) is associated with mucopolysaccharidosis type 6 (ClinVar).

How common is ARSB p.Leu82Pro (c.245T>C) in the general population?

ARSB p.Leu82Pro (c.245T>C) is very rare (popmax 0.00143%, afr) (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.Leu82Pro (c.245T>C)?

AlphaMissense predicts likely pathogenic (score 0.9042) — an in-silico prediction, not a clinical call.

ARSB p.Leu82Pro

c.245T>C · rs749465732 · VCV2169513

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9042 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00143%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 6

Computational evidence

Protein change
AlphaMissense	0.9042	likely pathogenic ✓ concordant with ClinVar
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -13.62	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 1.7, phastCons 1
Overall
CADD	30.0	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 0.00143% African / African-American · 1/70,056 alleles

Overall 0.00026% 4/1,539,482 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0034%	29,445
African / African-Americangrpmax	0.00143%	70,056
European (non-Finnish)	8.72e-05%	1,146,374

Remaining individuals 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: ARSB
Protein: p.Leu82Pro
Coding: c.245T>C
MANE Select: NM_020427 · reported on NM_000046
dbSNP: rs749465732
Type: single nucleotide variant
Location: chr5:78985004 (GRCh38)
Structure: AlphaFold pLDDT 84.32 · 2 PDB
Residue 82: a UniProt-annotated variant site (in mdm; uncertain significance; no effect on secretion); a disulfide bond

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.Leu82Gln Pathogenic ★ same residue
ARSB p.Leu82Val Likely pathogenic ★ ⚠ same residue
ARSB p.Leu82= Likely benign ★ 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-leu82pro (accessed [today's date]).

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