Is ARSB p.Ser42Gly (c.124A>G) pathogenic?

ARSB p.Ser42Gly (c.124A>G) is classified Uncertain significance in ARSB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0549); Very rare (popmax 8.97e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARSB p.Ser42Gly (c.124A>G)?

ARSB p.Ser42Gly (c.124A>G) is associated with Inborn genetic diseases, mucopolysaccharidosis type 6 (ClinVar).

How common is ARSB p.Ser42Gly (c.124A>G) in the general population?

ARSB p.Ser42Gly (c.124A>G) is very rare (popmax 8.97e-05%, nfe) (gnomAD).

What do computational predictors say about ARSB p.Ser42Gly (c.124A>G)?

AlphaMissense predicts likely benign (score 0.0549) — an in-silico prediction, not a clinical call.

ARSB p.Ser42Gly

c.124A>G · rs1250729156 · VCV906821

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0549 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.97e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0549	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -2.98	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 -2.6	GERP -2.6
Overall
CADD	8.35	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 8.97e-05% European (non-Finnish) · 1/1,115,056 alleles

Overall 0.000472% 7/1,482,968 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0191%	5,224
Remaining individualsnot grpmax-eligible	0.00178%	56,264
European (non-Finnish)grpmax	8.97e-05%	1,115,056

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser42Gly
Coding: c.124A>G
MANE Select: NM_020427 · reported on NM_000046
dbSNP: rs1250729156
Type: single nucleotide variant
Location: chr5:78985125 (GRCh38)
Structure: AlphaFold pLDDT 84.32 · 2 PDB
Residue 42: the upar/ly6 domain; a β-strand; 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

SLURP1 p.Arg42His Uncertain significance ★★ ⚠ same residue
SLURP1 p.Arg42Cys Uncertain significance ★ ⚠ 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-ser42gly (accessed [today's date]).

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