Is GUSB p.Arg216Trp (c.646C>T) pathogenic?

GUSB p.Arg216Trp (c.646C>T) is classified Pathogenic/Likely pathogenic in GUSB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-12-08). AlphaMissense: likely pathogenic (0.8783); Very rare (popmax 0.0011%, nfe); Associated with mucopolysaccharidosis type 7.

What condition is associated with GUSB p.Arg216Trp (c.646C>T)?

GUSB p.Arg216Trp (c.646C>T) is associated with mucopolysaccharidosis type 7 (ClinVar).

How common is GUSB p.Arg216Trp (c.646C>T) in the general population?

GUSB p.Arg216Trp (c.646C>T) is very rare (popmax 0.0011%, nfe) (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.Arg216Trp (c.646C>T)?

AlphaMissense predicts likely pathogenic (score 0.8783) — an in-silico prediction, not a clinical call.

GUSB p.Arg216Trp

c.646C>T · rs121918174 · VCV895

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 7

Computational evidence

Protein change
AlphaMissense	0.8783	likely pathogenic ✓ concordant with ClinVar
REVEL	0.984	strongly pathogenic-leaning
SaProt	LLR -15.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,069 bp · p 0.83 · regional, not allelic
Overall
CADD	33.0	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 0.0011% European (non-Finnish) · 13/1,179,478 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00155% 25/1,613,444 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0172%	5,822
European (non-Finnish)grpmax	0.0011%	90,729
South Asian	0.0011%	91,068

Finnish 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: GUSB
Protein: p.Arg216Trp
Coding: c.646C>T
MANE Select: NM_000181
dbSNP: rs121918174
Type: single nucleotide variant
Location: chr7:65979477 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 2 PDB
Residue 216: a UniProt-annotated variant site (in mps7)

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.Arg216Gln 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.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-arg216trp (accessed [today's date]).

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