Is ARSB p.Pro454= (c.1362G>A) pathogenic?

ARSB p.Pro454= (c.1362G>A) is classified Benign in ARSB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 16.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with mucopolysaccharidosis type 6.

What condition is associated with ARSB p.Pro454= (c.1362G>A)?

ARSB p.Pro454= (c.1362G>A) is associated with mucopolysaccharidosis type 6 (ClinVar).

How is Mucopolysaccharidosis type 6 inherited?

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

ARSB p.Pro454=

Q: How common is ARSB p.Pro454= (c.1362G>A) in the general population?

ARSB p.Pro454= (c.1362G>A) is common (popmax 16.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1362G>A · rs35757003 · VCV354307

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 16.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

mucopolysaccharidosis type 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.7
Overall
CADD	0.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.8% African / African-American · 12,555/74,928 alleles

Filtering AF 16.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.4%

Overall 0.897% 14,482/1,613,940 alleles · common exomes 7,424/1,461,838 · genomes 7,058/152,102 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	16.8%	6
Middle Eastern	1.7%	59
Remaining individualsnot grpmax-eligible	1.14%	88
Admixed American	0.932%	107
South Asian	0.111%	902
East Asian	0.0602%	1,662
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
European (non-Finnish)	0.035%	2,857

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.Pro454=
Coding: c.1362G>A
MANE Select: NM_000046
dbSNP: rs35757003
Type: single nucleotide variant
Location: chr5:78780637 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 1 PDB
Residue 454: a turn

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 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
ARSB c.1143-8T>G Pathogenic/Likely pathogenic ★★ same condition
ARSB c.1213+6T>C 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-pro454 (accessed [today's date]).

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