Is ARSB p.Pro15Ala (c.43C>G) pathogenic?

ARSB p.Pro15Ala (c.43C>G) is classified Uncertain significance in ARSB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.0579); Ultra-rare (popmax 0.0698%, eas); Associated with mucopolysaccharidosis type 6.

What condition is associated with ARSB p.Pro15Ala (c.43C>G)?

ARSB p.Pro15Ala (c.43C>G) is associated with mucopolysaccharidosis type 6 (ClinVar).

How common is ARSB p.Pro15Ala (c.43C>G) in the general population?

ARSB p.Pro15Ala (c.43C>G) is ultra-rare (popmax 0.0698%, eas) (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.Pro15Ala (c.43C>G)?

AlphaMissense predicts likely benign (score 0.0579) — an in-silico prediction, not a clinical call.

ARSB p.Pro15Ala

c.43C>G · rs778159305 · VCV971367

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0579 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0698%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 6

Computational evidence

Protein change
AlphaMissense	0.0579	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.001, phastCons 0.4
Overall
CADD	6.119	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 0.0698% East Asian · 23/32,968 alleles

Filtering AF 0.0476% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0404%

Overall 0.00182% 25/1,371,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0698%	1,433
Remaining individualsnot grpmax-eligible	0.00385%	25,970

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.Pro15Ala
Coding: c.43C>G
MANE Select: NM_020427 · reported on NM_000046
dbSNP: rs778159305
Type: single nucleotide variant
Location: chr5:78985206 (GRCh38)
Structure: AlphaFold pLDDT 84.32 · 2 PDB
Residue 15: a UniProt-annotated variant site (in mdm; no expression of the protein)

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

SLURP1 p.Trp15Arg 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
ARSB c.1143-8T>G 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-pro15ala (accessed [today's date]).

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