Is GLB1 p.Pro513Ser (c.1537C>T) pathogenic?

GLB1 p.Pro513Ser (c.1537C>T) is classified Uncertain significance in GLB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely benign (0.1393); Very rare (popmax 0.000254%, nfe); Associated with mucopolysaccharidosis type 4B.

What condition is associated with GLB1 p.Pro513Ser (c.1537C>T)?

GLB1 p.Pro513Ser (c.1537C>T) is associated with mucopolysaccharidosis type 4B, GM1 gangliosidosis (ClinVar).

How common is GLB1 p.Pro513Ser (c.1537C>T) in the general population?

GLB1 p.Pro513Ser (c.1537C>T) is very rare (popmax 0.000254%, nfe) (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.Pro513Ser (c.1537C>T)?

AlphaMissense predicts likely benign (score 0.1393) — an in-silico prediction, not a clinical call.

GLB1 p.Pro513Ser

c.1537C>T · rs1459678748 · VCV2151807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1393 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mucopolysaccharidosis type 4B

Computational evidence

Protein change
AlphaMissense	0.1393	likely benign
REVEL	0.414	indeterminate
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 100 kb · p 0.044 · regional, not allelic
Overall
CADD	19.13	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 0.000254% European (non-Finnish) · 3/1,180,040 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,048 alleles · very rare exomes 3/1,461,870 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.000254%	393,346

Remaining individuals 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.Pro513Ser
Coding: c.1537C>T
MANE Select: NM_000404
dbSNP: rs1459678748
Type: single nucleotide variant
Location: chr3:33014253 (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 513: a β-strand

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 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
GLB1 c.245+1G>A Pathogenic ★★ same condition
GLB1 c.396+2T>C Pathogenic/Likely pathogenic ★★ same condition
GLB1 c.397-1G>A 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-pro513ser (accessed [today's date]).

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