Is GLB1 p.Arg595Pro (c.1784G>C) pathogenic?

GLB1 p.Arg595Pro (c.1784G>C) is classified Likely pathogenic in GLB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-01). AlphaMissense: likely pathogenic (0.7621); Very rare (popmax 0.00167%, amr).

How common is GLB1 p.Arg595Pro (c.1784G>C) in the general population?

GLB1 p.Arg595Pro (c.1784G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about GLB1 p.Arg595Pro (c.1784G>C)?

AlphaMissense predicts likely pathogenic (score 0.7621) — an in-silico prediction, not a clinical call.

GLB1 p.Arg595Pro

c.1784G>C · rs199694629 · VCV932727

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.7621	likely pathogenic ✓ concordant with ClinVar
REVEL	0.374	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 -0.24	GERP -1.5
Regional constraint	o/e 0.93	unconstrained · MANE · 100 kb · p 0.044 · regional, not allelic
Overall
CADD	21.7	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 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,906 alleles · very rare exomes 2/1,461,764 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
European (non-Finnish)	0.000169%	590,012

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.Arg595Pro
Coding: c.1784G>C
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

Similar variants

GLB1 p.Arg595Gln Uncertain significance ★★ ⚠ same residue
GLB1 p.Arg595Trp Uncertain significance ★★ same residue
GLB1 p.Arg595= Likely benign ★ same residue
GLB1 c.1144-2A>G Pathogenic/Likely pathogenic ★★ same type
GLB1 c.1233+1G>A Pathogenic/Likely pathogenic ★★ same type
GLB1 c.1347+1G>T Likely pathogenic ★★ same type
GLB1 c.1479+1G>A Pathogenic ★★ same type
GLB1 c.1480-1G>C Pathogenic/Likely pathogenic ★★ same type

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-arg595pro (accessed [today's date]).

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