Is ARSB p.Arg434Ter (c.1299dup) pathogenic?

ARSB p.Arg434Ter (c.1299dup) is classified Pathogenic/Likely pathogenic in ARSB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-25). Very rare (popmax 0.00534%, afr); Associated with mucopolysaccharidosis type 6.

What condition is associated with ARSB p.Arg434Ter (c.1299dup)?

ARSB p.Arg434Ter (c.1299dup) is associated with mucopolysaccharidosis type 6 (ClinVar).

How common is ARSB p.Arg434Ter (c.1299dup) in the general population?

ARSB p.Arg434Ter (c.1299dup) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Mucopolysaccharidosis type 6 inherited?

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

ARSB p.Arg434Ter

c.1299dup · rs1355071930 · VCV852181

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

mucopolysaccharidosis type 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.77	GERP 0.85, phastCons 1
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,916 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00263% 4/152,186 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.Arg434Ter
Coding: c.1299dup
MANE Select: NM_020427 · reported on NM_000046
dbSNP: rs1355071930
Type: Duplication
Location: chr5:78781888 (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.Arg434Ile Uncertain significance ★ ⚠ same residue
ARSB p.Ala41fs Pathogenic/Likely pathogenic ★★ same condition
ARSB p.Pro123fs Pathogenic/Likely pathogenic ★★ same condition
ARSB p.Ser120fs Pathogenic/Likely pathogenic ★★ same condition
ARSB p.Val22fs Pathogenic/Likely pathogenic ★★ same condition
ARSB c.-310-3dup Benign ★★ same condition
ARSB p.Ala267fs Likely pathogenic ★ same condition
ARSB p.Arg388fs 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-arg434ter (accessed [today's date]).

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