Is GLB1 p.Arg595Trp (c.1783C>T) pathogenic?

GLB1 p.Arg595Trp (c.1783C>T) is classified Uncertain significance in GLB1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-10-26). AlphaMissense: likely benign (0.1917); Ultra-rare (popmax 0.0833%, amr); Associated with Inborn genetic diseases.

What condition is associated with GLB1 p.Arg595Trp (c.1783C>T)?

GLB1 p.Arg595Trp (c.1783C>T) is associated with Inborn genetic diseases, GM1 gangliosidosis type 1, GM1 gangliosidosis type 2 (ClinVar).

How common is GLB1 p.Arg595Trp (c.1783C>T) in the general population?

GLB1 p.Arg595Trp (c.1783C>T) is ultra-rare (popmax 0.0833%, amr) (gnomAD).

What do computational predictors say about GLB1 p.Arg595Trp (c.1783C>T)?

AlphaMissense predicts likely benign (score 0.1917) — an in-silico prediction, not a clinical call.

GLB1 p.Arg595Trp

c.1783C>T · rs201807974 · VCV550288

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1917 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0833%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1917	likely benign
REVEL	0.615	indeterminate
SaProt	—	withheld · numbering disagrees past residue 521 · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5	GERP 0.74
Regional constraint	o/e 0.93	unconstrained · MANE · 100 kb · p 0.044 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0833% Admixed American · 50/60,030 alleles

Filtering AF 0.0648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0583%

Overall 0.00663% 107/1,614,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0833%	1,201
Remaining individualsnot grpmax-eligible	0.008%	12,500
East Asian	0.00446%	22,435
European (non-Finnish)	0.00398%	25,107
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00266%	37,525

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: GLB1
Protein: p.Arg595Trp
Coding: c.1783C>T
MANE Select: NM_000404
dbSNP: rs201807974
Type: single nucleotide variant
Location: chr3:32997296 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.19 · 8 PDB
Residue 595: a UniProt-annotated variant site (reduction of galactosidase activity); a turn

Full GLB1 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: GM1 gangliosidosis type 1 GM1 gangliosidosis type 2 GM1 gangliosidosis type 3 mucopolysaccharidosis type 4B GM1 gangliosidosis

Similar variants

GLB1 p.Arg595Gln Uncertain significance ★★ ⚠ same residue
GLB1 p.Arg595= Likely benign ★ same residue
GLB1 p.Arg595Pro Likely pathogenic ★ same residue
GLB1 c.1144-2A>G Pathogenic/Likely pathogenic ★★ same condition
GLB1 c.1233+1G>A Pathogenic/Likely pathogenic ★★ same condition
GLB1 c.1347+1G>T Likely pathogenic ★★ same condition
GLB1 c.1479+1G>A Pathogenic ★★ same condition
GLB1 c.1480-1G>C 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/glb1-p-arg595trp (accessed [today's date]).

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