Is GUSB p.Arg577Cys (c.1729C>T) pathogenic?

GUSB p.Arg577Cys (c.1729C>T) is classified Uncertain significance in GUSB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-05). AlphaMissense: ambiguous (0.3819); Very rare (popmax 0.00223%, eas); Associated with mucopolysaccharidosis type 7.

What condition is associated with GUSB p.Arg577Cys (c.1729C>T)?

GUSB p.Arg577Cys (c.1729C>T) is associated with mucopolysaccharidosis type 7 (ClinVar).

How common is GUSB p.Arg577Cys (c.1729C>T) in the general population?

GUSB p.Arg577Cys (c.1729C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Mucopolysaccharidosis type 7 inherited?

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

What do computational predictors say about GUSB p.Arg577Cys (c.1729C>T)?

AlphaMissense predicts ambiguous (score 0.3819) — an in-silico prediction, not a clinical call.

GUSB p.Arg577Cys

c.1729C>T · rs747104326 · VCV1899897

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

mucopolysaccharidosis type 7

Computational evidence

Protein change
AlphaMissense	0.3819	ambiguous
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -9.16	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 15 kb · p 3.7e-08 · regional, not allelic
Overall
CADD	29.7	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

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,611,348 alleles · very rare exomes 5/1,459,052 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
South Asian	0.0011%	90,972
European (non-Finnish)	0.000254%	393,085

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: GUSB
Protein: p.Arg577Cys
Coding: c.1729C>T
MANE Select: NM_000181
dbSNP: rs747104326
Type: single nucleotide variant
Location: chr7:65964383 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 2 PDB
Residue 577: a turn; a UniProt-annotated variant site (in mps7; loss of activity)

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

Disease context

mucopolysaccharidosis type 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mucopolysaccharidosis type 7 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Antenatal, Childhood, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

GUSB p.Arg577Leu Likely pathogenic ★ ⚠ same residue
GUSB c.1244+1G>A Pathogenic ★★ same condition
GUSB c.581+1G>A Pathogenic/Likely pathogenic ★★ same condition
GUSB c.724+1G>T Pathogenic/Likely pathogenic ★★ same condition
GUSB p.Ala619Val Pathogenic/Likely pathogenic ★★ same condition
GUSB p.Arg110Ter Pathogenic/Likely pathogenic ★★ same condition
GUSB p.Arg167Ter Pathogenic/Likely pathogenic ★★ same condition
GUSB p.Arg216Trp 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/gusb-p-arg577cys (accessed [today's date]).

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