Is GLB1 p.Arg68Pro (c.203G>C) pathogenic?

GLB1 p.Arg68Pro (c.203G>C) is classified Likely pathogenic in GLB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: likely pathogenic (0.9842); Absent from gnomAD v4.1.

How common is GLB1 p.Arg68Pro (c.203G>C) in the general population?

GLB1 p.Arg68Pro (c.203G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLB1 p.Arg68Pro (c.203G>C)?

AlphaMissense predicts likely pathogenic (score 0.9842) — an in-silico prediction, not a clinical call.

GLB1 p.Arg68Pro

c.203G>C · VCV4081424

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9842 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9842	likely pathogenic ✓ concordant with ClinVar · top 1% in GLB1
REVEL	0.984	strongly pathogenic-leaning
SaProt	LLR -12.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 100 kb · p 0.044 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GLB1
Protein: p.Arg68Pro
Coding: c.203G>C
MANE Select: NM_000404
Type: single nucleotide variant
Location: chr3:33072586 (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 68: an α-helix; a UniProt-annotated variant site (in gm1g2; 7.4% of wild-type galactosidase activity); a UniProt-annotated variant site (in gm1g2 and gm1g1; loss of galactosidase activity)

Full GLB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GLB1 p.Arg68Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
GLB1 p.Arg68Trp Pathogenic ★★ same residue
GLB1 p.Arg68Gly Likely pathogenic ★ same residue
GLB1 p.Arg68Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TMPPE p.Val68Gly Uncertain significance ★ ⚠ same residue
GLB1 p.Arg68= Likely benign ★ same residue
GLB1 c.1144-2A>G Pathogenic/Likely pathogenic ★★ same type
GLB1 c.1233+1G>A 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-arg68pro (accessed [today's date]).

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