Is ARSB p.His430Arg (c.1289A>G) pathogenic?

ARSB p.His430Arg (c.1289A>G) is classified Likely pathogenic in ARSB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-01). AlphaMissense: likely benign (0.2039); Very rare (popmax 0.000508%, nfe); Associated with mucopolysaccharidosis type 6.

What condition is associated with ARSB p.His430Arg (c.1289A>G)?

ARSB p.His430Arg (c.1289A>G) is associated with mucopolysaccharidosis type 6 (ClinVar).

How common is ARSB p.His430Arg (c.1289A>G) in the general population?

ARSB p.His430Arg (c.1289A>G) is very rare (popmax 0.000508%, nfe) (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.His430Arg (c.1289A>G)?

AlphaMissense predicts likely benign (score 0.2039) — an in-silico prediction, not a clinical call.

ARSB p.His430Arg

c.1289A>G · rs1171277553 · VCV559698

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2039 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 6

Computational evidence

Protein change
AlphaMissense	0.2039	likely benign ⚠ discordant with ClinVar
REVEL	0.702	pathogenic-leaning
SaProt	LLR -2.77	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Overall
CADD	21.5	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 0.000508% European (non-Finnish) · 6/1,179,966 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,818 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.His430Arg
Coding: c.1289A>G
MANE Select: NM_000046
dbSNP: rs1171277553
Type: single nucleotide variant
Location: chr5:78781899 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 1 PDB
Residue 430: a disulfide bond; a β-strand

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.His430Asn Uncertain significance ★ same residue
ARSB p.His430fs Likely pathogenic ★ 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
ARSB c.1143-1G>C 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-his430arg (accessed [today's date]).

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