# NM_000404.4(GLB1):c.501C>T (p.Pro167=)

https://sugi.bio/variant/glb1-p-pro167

## Summary

**GLB1 p.Pro167= (c.501C>T)** is classified **Uncertain significance** in GLB1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-02-02). No allele count reported in gnomAD v4.1 (AN 1,586,160); Associated with GM1 gangliosidosis type 3.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs1553611799 · 1 submitter · 4 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,586,160)

## For patients & families {#patients}

This is a change in the GLB1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to GM1 gangliosidosis type 3.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | GLB1 is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of GM1 gangliosidosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Coarse facial features — Very frequent (99-80%)
- Depressed nasal ridge — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)
- Abnormal diaphysis morphology — Very frequent (99-80%)
- Abnormal metaphysis morphology — Very frequent (99-80%)
- Hyperreflexia — Very frequent (99-80%)
- Splenomegaly — Very frequent (99-80%)
- Weight loss — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002431/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GLB1](https://sugi.bio/atlas/gene/GLB1/) |
| Protein change (HGVS p.) | p.Pro167= |
| Coding change (HGVS c.) | c.501C>T |
| MANE Select transcript | [NM_000404](https://www.ncbi.nlm.nih.gov/nuccore/NM_000404) |
| dbSNP | [rs1553611799](https://www.ncbi.nlm.nih.gov/snp/rs1553611799/) |
| Variant type | single nucleotide variant |
| Location | chr3:33065514-33065514 (GRCh38) |
| ClinVar | [VCV556506](https://www.ncbi.nlm.nih.gov/clinvar/variation/556506/) |

**All HGVS expressions:** `NC_000003.11:g.33107006G>A`, `NC_000003.12:g.33065514G>A`, `NG_009005.1:g.36689C>T`, `NM_000404.4:c.501C>T`, `NM_001079811.3:c.411C>T`, `NM_001135602.3:c.289C>T`, `NM_001317040.2:c.645C>T`, `NM_001393580.1:c.501C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.366, GERP 0.094, phastCons 0.98 — weakly conserved position
- CADD: **PHRED 9.91**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,586,160)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GLB1** population constraint: LOEUF 0.938, pLI 2.9564e-15, missense-Z 1.1365; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **GM1 gangliosidosis** — Definitive (AR)
- **mucopolysaccharidosis type 4B** — Definitive (AR)

## Protein context {#protein}

Residue **167** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 90.19, 85% of residues very-high.

**8 experimental structure(s)** (PDB): [3THC](https://www.rcsb.org/structure/3THC), [3THD](https://www.rcsb.org/structure/3THD), [3WEZ](https://www.rcsb.org/structure/3WEZ), [3WF0](https://www.rcsb.org/structure/3WF0), [3WF1](https://www.rcsb.org/structure/3WF1), [3WF2](https://www.rcsb.org/structure/3WF2) — incl. mutant structure 3WF3.

## What this gene does {#gene-function}

*Describes the biological roles of GLB1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GLB1's established molecular role includes beta-galactosidase activity. In Reactome, GLB1 is annotated in disease pathway(s) including **Defective NEU1 causes sialidosis**, **MPS IV - Morquio syndrome B (CS/DS degradation)**.

**Disease mechanism (Reactome):** GLB1 loss or alteration is curated in [Defective NEU1 causes sialidosis](https://reactome.org/content/detail/R-HSA-4341670), [MPS IV - Morquio syndrome B (CS/DS degradation)](https://reactome.org/content/detail/R-HSA-9953111), [MPS IV - Morquio syndrome B (Keratin metabolism)](https://reactome.org/content/detail/R-HSA-2206308).

### Pathways affected {#pathways}

GLB1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective NEU1 causes sialidosis](https://reactome.org/content/detail/R-HSA-4341670) | curated |
| ⚕ [MPS IV - Morquio syndrome B (CS/DS degradation)](https://reactome.org/content/detail/R-HSA-9953111) | curated |
| ⚕ [MPS IV - Morquio syndrome B (Keratin metabolism)](https://reactome.org/content/detail/R-HSA-2206308) | curated |
| [CS/DS degradation](https://reactome.org/content/detail/R-HSA-2024101) | curated |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [Keratan sulfate degradation](https://reactome.org/content/detail/R-HSA-2022857) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Sialic acid metabolism](https://reactome.org/content/detail/R-HSA-4085001) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** beta-galactosidase activity, protein homodimerization activity.

**Biological process:** carbohydrate metabolic process, glycoprotein catabolic process, ganglioside catabolic process, keratan sulfate proteoglycan catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2018-02-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2018-02-02 |

## Associated conditions {#conditions}

[GM1 gangliosidosis type 3](https://sugi.bio/atlas/disease/gm1-gangliosidosis-type-3/), [GM1 gangliosidosis type 1](https://sugi.bio/atlas/disease/gm1-gangliosidosis-type-1/), [GM1 gangliosidosis type 2](https://sugi.bio/atlas/disease/gm1-gangliosidosis-type-2/), [mucopolysaccharidosis type 4B](https://sugi.bio/atlas/disease/mucopolysaccharidosis-type-4b/).

**Reported phenotype names (ClinVar):** GM1 gangliosidosis type 3, GM1 gangliosidosis type 2, Infantile GM1 gangliosidosis, Mucopolysaccharidosis, MPS-IV-B, GANGLIOSIDOSIS, GENERALIZED GM1, ADULT TYPE, GANGLIOSIDOSIS, GENERALIZED GM1, CHRONIC TYPE, GANGLIOSIDOSIS, GENERALIZED GM1, TYPE III, GM1-GANGLIOSIDOSIS, TYPE III, Beta-galactosidase deficiency, Adult GM1 gangliosidosis.

## Same-residue context {#hotspot}

Residue **167** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GLB1 p.Pro167fs](/variant/glb1-p-pro167fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GLB1 variant pages (same residue, condition, or type): [GLB1 c.1144-2A>G](/variant/glb1-c-1144-minus-2a-g), [GLB1 c.1233+1G>A](/variant/glb1-c-1233-plus-1g-a), [GLB1 c.1347+1G>T](/variant/glb1-c-1347-plus-1g-t), [GLB1 c.1479+1G>A](/variant/glb1-c-1479-plus-1g-a), [GLB1 c.1480-1G>C](/variant/glb1-c-1480-minus-1g-c), [GLB1 c.1480-2A>G](/variant/glb1-c-1480-minus-2a-g), [GLB1 c.245+1G>A](/variant/glb1-c-245-plus-1g-a), [GLB1 c.396+2T>C](/variant/glb1-c-396-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 556506). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*