Is GLB1 p.Pro2Leu (c.5C>T) pathogenic?

GLB1 p.Pro2Leu (c.5C>T) is classified Uncertain significance in GLB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely benign (0.12); Very rare (popmax 0.00334%, amr); Associated with mucopolysaccharidosis type 4B.

What condition is associated with GLB1 p.Pro2Leu (c.5C>T)?

GLB1 p.Pro2Leu (c.5C>T) is associated with mucopolysaccharidosis type 4B, GM1 gangliosidosis (ClinVar).

How common is GLB1 p.Pro2Leu (c.5C>T) in the general population?

GLB1 p.Pro2Leu (c.5C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

How is Mucopolysaccharidosis type 4 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GLB1 p.Pro2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

GLB1 p.Pro2Leu

c.5C>T · rs779544911 · VCV2194800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 4B

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -3.5
Regional constraint	o/e 0.93	unconstrained · MANE · 100 kb · p 0.044 · regional, not allelic
Overall
CADD	9.708	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,898 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000744% 12/1,612,538 alleles · very rare exomes 12/1,460,208 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,949
Remaining individualsnot grpmax-eligible	0.0016%	62,418
South Asian	0.0011%	90,954
European (non-Finnish)	0.000679%	147,382

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_000404
dbSNP: rs779544911
Type: single nucleotide variant
Location: chr3:33097081 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.19 · 8 PDB

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

Disease context

mucopolysaccharidosis type 4B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: GM1 gangliosidosis

For Mucopolysaccharidosis type 4 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Sweden)

Similar variants

GLB1 p.Pro2Thr Uncertain significance ★★ ⚠ same residue
GLB1 p.Pro2Ala Uncertain significance ★ ⚠ same residue
GLB1 p.Pro2= Likely benign ★ 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.1480-2A>G 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-pro2leu (accessed [today's date]).

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