Is ARSB p.Thr140Pro (c.418A>C) pathogenic?

ARSB p.Thr140Pro (c.418A>C) is classified Uncertain significance in ARSB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-01). AlphaMissense: ambiguous (0.4819); Absent from gnomAD v4.1; Associated with mucopolysaccharidosis type 6.

What condition is associated with ARSB p.Thr140Pro (c.418A>C)?

ARSB p.Thr140Pro (c.418A>C) is associated with mucopolysaccharidosis type 6 (ClinVar).

How common is ARSB p.Thr140Pro (c.418A>C) in the general population?

ARSB p.Thr140Pro (c.418A>C) is absent from gnomAD v4.1 (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.Thr140Pro (c.418A>C)?

AlphaMissense predicts ambiguous (score 0.4819) — an in-silico prediction, not a clinical call.

ARSB p.Thr140Pro

c.418A>C · rs1554088058 · VCV559780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4819 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mucopolysaccharidosis type 6

Computational evidence

Protein change
AlphaMissense	0.4819	ambiguous
REVEL	0.986	strongly pathogenic-leaning
SaProt	LLR -12.78	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Overall
CADD	29.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARSB
Protein: p.Thr140Pro
Coding: c.418A>C
MANE Select: NM_000046
dbSNP: rs1554088058
Type: single nucleotide variant
Location: chr5:78969087 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 1 PDB
Residue 140: 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 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-thr140pro (accessed [today's date]).

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