# NM_000404.4(GLB1):c.1873C>T (p.Pro625Ser)

https://sugi.bio/variant/glb1-p-pro625ser

## Summary

**GLB1 p.Pro625Ser (c.1873C>T)** is classified **Uncertain significance** in GLB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.1828); Very rare (popmax 0.0011%, sas); Associated with mucopolysaccharidosis type 4B.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs755581184 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0011%, 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 mucopolysaccharidosis type 4B.

*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, Infancy |
| Prevalence | <1 / 1 000 000 (Sweden) |
| Diagnostic panels | GLB1 is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Mucopolysaccharidosis type 4** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the dentition — Very frequent (99-80%)
- Hearing impairment — Very frequent (99-80%)
- Short neck — Very frequent (99-80%)
- Pectus carinatum — Very frequent (99-80%)
- Abnormal rib morphology — Very frequent (99-80%)
- Abnormal metaphysis morphology — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Delayed skeletal maturation — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003786/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.Pro625Ser |
| Coding change (HGVS c.) | c.1873C>T |
| MANE Select transcript | [NM_000404](https://www.ncbi.nlm.nih.gov/nuccore/NM_000404) |
| dbSNP | [rs755581184](https://www.ncbi.nlm.nih.gov/snp/rs755581184/) |
| Variant type | single nucleotide variant |
| Location | chr3:32997206-32997206 (GRCh38) |
| ClinVar | [VCV1414271](https://www.ncbi.nlm.nih.gov/clinvar/variation/1414271/) |

**All HGVS expressions:** `NC_000003.11:g.33038698G>A`, `NC_000003.12:g.32997206G>A`, `NG_009005.1:g.104997C>T`, `NM_000404.4:c.1873C>T`, `NM_001079811.3:c.1783C>T`, `NM_001135602.3:c.1480C>T`, `NM_001317040.2:c.2017C>T`, `NM_001393580.1:c.1734+16850C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1828)
- REVEL 0.53 (indeterminate)
- Conservation: phyloP 7.423, GERP -0.447, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** withheld — SaProt scored this protein on a different isoform than AlphaMissense numbered the variant on, and the two diverge from residue 521, so a score under this position number would describe a different residue.
- CADD: **PHRED 19.64**. 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: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/91,094 in the highest group · 5/1,614,084 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,094 |
| European (non-Finnish) | 0.000339% | 295,012 |

*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}


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)*, last evaluated 2023-08-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Mucopolysaccharidosis, MPS-IV-B, GM1 gangliosidosis, MORQUIO SYNDROME B, Mucopolysaccharidosis Type IVB (Morquio B Disease), Mucopolysaccharidosis type 4B, Mucopolysaccharidosis type IVB (Morquio), MPS IVB, Mucopolysaccharidosis type IV B, Mucopolysaccharidosis Type IVB.

## 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.1480-2A>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), [GLB1 c.397-1G>A](/variant/glb1-c-397-minus-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 1414271). 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.*