# NM_000404.4(GLB1):c.1099C>T (p.Pro367Ser)

https://sugi.bio/variant/glb1-p-pro367ser

## Summary

**GLB1 p.Pro367Ser (c.1099C>T)** is classified **Uncertain significance** in GLB1 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.1057); Very rare (popmax 0.00113%, sas); Associated with GM1 gangliosidosis type 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1697636883 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00113%, sas)

## 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 1.

*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/0006479/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.Pro367Ser |
| Coding change (HGVS c.) | c.1099C>T |
| MANE Select transcript | [NM_000404](https://www.ncbi.nlm.nih.gov/nuccore/NM_000404) |
| dbSNP | [rs1697636883](https://www.ncbi.nlm.nih.gov/snp/rs1697636883/) |
| Variant type | single nucleotide variant |
| Location | chr3:33024295-33024295 (GRCh38) |
| ClinVar | [VCV1332870](https://www.ncbi.nlm.nih.gov/clinvar/variation/1332870/) |

**All HGVS expressions:** `NC_000003.11:g.33065787G>A`, `NC_000003.12:g.33024295G>A`, `NG_009005.1:g.77908C>T`, `NM_000404.4:c.1099C>T`, `NM_001079811.3:c.1009C>T`, `NM_001135602.3:c.706C>T`, `NM_001317040.2:c.1243C>T`, `NM_001393580.1:c.1099C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1057)
- REVEL 0.646 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.698 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 11.718, GERP 1.92, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.5**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (32,997,048–33,097,085), spanning 100,037 bp. Chi-square p 0.044. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GLB1 (1,086 scored positions, the nearest 26 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00113%** (sas) · 1/88,806 in the highest group · 1/1,570,420 alleles overall — very rare (popmax 0.00113%, sas).

*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 **367** 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 Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Uncertain significance | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[GM1 gangliosidosis type 1](https://sugi.bio/atlas/disease/gm1-gangliosidosis-type-1/).

**Reported phenotype names (ClinVar):** Infantile GM1 gangliosidosis, Gangliosidosis, Generalized GM1, Type 1, GM1-gangliosidosis, type I, Gangliosidosis, generalized GM1, infantile form, GLB1 deficiency, GM1 gangliosidosis type 1.

## Similar variants {#similar}

Related GLB1 variant pages (same residue, condition, or type): [GLB1 p.Pro367=](/variant/glb1-p-pro367), [GLB1 p.Pro367Leu](/variant/glb1-p-pro367leu), [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.1480-2A>G](/variant/glb1-c-1480-minus-2a-g), [GLB1 c.245+1G>A](/variant/glb1-c-245-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1332870). 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.*