Is ARSB p.Pro228Leu (c.683C>T) pathogenic?

ARSB p.Pro228Leu (c.683C>T) is classified Uncertain significance in ARSB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-10). AlphaMissense: likely benign (0.0803); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ARSB p.Pro228Leu (c.683C>T)?

ARSB p.Pro228Leu (c.683C>T) is associated with Inborn genetic diseases, mucopolysaccharidosis type 6 (ClinVar).

How common is ARSB p.Pro228Leu (c.683C>T) in the general population?

ARSB p.Pro228Leu (c.683C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ARSB p.Pro228Leu (c.683C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

ARSB p.Pro228Leu

c.683C>T · rs1183289497 · VCV2418120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.544	indeterminate
SaProt	LLR -3.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,910 alleles

Overall 0.000124% 2/1,613,612 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,910
European (non-Finnish)	8.48e-05%	1,179,695

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.Pro228Leu
Coding: c.683C>T
MANE Select: NM_000046
dbSNP: rs1183289497
Type: single nucleotide variant
Location: chr5:78964423 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 1 PDB
Residue 228: a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mucopolysaccharidosis type 6

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-pro228leu (accessed [today's date]).

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