Is GUSB p.Arg66Trp (c.196C>T) pathogenic?

GUSB p.Arg66Trp (c.196C>T) is classified Uncertain significance in GUSB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-18). AlphaMissense: likely benign (0.144); Ultra-rare (popmax 0.0234%, amr); Associated with mucopolysaccharidosis type 7.

What condition is associated with GUSB p.Arg66Trp (c.196C>T)?

GUSB p.Arg66Trp (c.196C>T) is associated with mucopolysaccharidosis type 7 (ClinVar).

How common is GUSB p.Arg66Trp (c.196C>T) in the general population?

GUSB p.Arg66Trp (c.196C>T) is ultra-rare (popmax 0.0234%, amr) (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.Arg66Trp (c.196C>T)?

AlphaMissense predicts likely benign (score 0.144) — an in-silico prediction, not a clinical call.

GUSB p.Arg66Trp

c.196C>T · rs776085845 · VCV1461737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.144 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mucopolysaccharidosis type 7

Computational evidence

Protein change
AlphaMissense	0.144	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.30	donor gain · deltas
Constraint at this position
Conservation	phyloP -0.15	GERP -3.2
Regional constraint	o/e 1.01	unconstrained · MANE · 6,069 bp · p 0.83 · regional, not allelic
Overall
CADD	23.7	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 0.0234% Admixed American · 14/59,864 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.000995% 16/1,607,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0234%	4,276
European (non-Finnish)	0.00017%	589,438

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.Arg66Trp
Coding: c.196C>T
MANE Select: NM_000181
dbSNP: rs776085845
Type: single nucleotide variant
Location: chr7:65981988 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 2 PDB

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 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
GUSB p.Arg357Ter 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-arg66trp (accessed [today's date]).

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