Is GLB1 p.Arg595Gln (c.1784G>A) pathogenic?

GLB1 p.Arg595Gln (c.1784G>A) is classified Uncertain significance in GLB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-10). AlphaMissense: likely benign (0.0911); Ultra-rare (popmax 0.0166%, mid); Associated with Inborn genetic diseases.

What condition is associated with GLB1 p.Arg595Gln (c.1784G>A)?

GLB1 p.Arg595Gln (c.1784G>A) is associated with Inborn genetic diseases, GM1 gangliosidosis type 1, GM1 gangliosidosis type 2 (ClinVar).

How common is GLB1 p.Arg595Gln (c.1784G>A) in the general population?

GLB1 p.Arg595Gln (c.1784G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about GLB1 p.Arg595Gln (c.1784G>A)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

GLB1 p.Arg595Gln

c.1784G>A · rs199694629 · VCV1210419

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.23	benign-leaning
SaProt	—	withheld · numbering disagrees past residue 521 · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24	GERP -1.5
Regional constraint	o/e 0.93	unconstrained · MANE · 100 kb · p 0.044 · regional, not allelic
Overall
CADD	19.47	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,008 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00304% 49/1,613,906 alleles · ultra-rare exomes 38/1,461,764 · genomes 11/152,142 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0328%	3,049
Middle Easterngrpmax	0.0166%	6,008
Admixed American	0.00833%	12,000
South Asian	0.00769%	13,011
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.0011%	90,771

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: GLB1
Protein: p.Arg595Gln
Coding: c.1784G>A
MANE Select: NM_000404
dbSNP: rs199694629
Type: single nucleotide variant
Location: chr3:32997295 (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.Arg595Trp 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-arg595gln (accessed [today's date]).

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