# NM_000404.4(GLB1):c.12C>T (p.Phe4=)

https://sugi.bio/variant/glb1-p-phe4

## Summary

**GLB1 p.Phe4= (c.12C>T)** is classified **Likely benign** in GLB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-27). Very rare (popmax 0.00401%, afr); Associated with mucopolysaccharidosis type 4B.

**At a glance:** Likely benign · review: Single submitter · rsID rs777282849 · 1 submitter · 2 linked conditions · very rare (popmax 0.00401%, afr)

## For patients & families {#patients}

This is a change in the GLB1 gene that is classified as likely benign — not considered disease-causing, 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.Phe4= |
| Coding change (HGVS c.) | c.12C>T |
| MANE Select transcript | [NM_000404](https://www.ncbi.nlm.nih.gov/nuccore/NM_000404) |
| dbSNP | [rs777282849](https://www.ncbi.nlm.nih.gov/snp/rs777282849/) |
| Variant type | single nucleotide variant |
| Location | chr3:33097074-33097074 (GRCh38) |
| ClinVar | [VCV2940136](https://www.ncbi.nlm.nih.gov/clinvar/variation/2940136/) |

**All HGVS expressions:** `NC_000003.11:g.33138566G>A`, `NC_000003.12:g.33097074G>A`, `NG_009005.2:g.5072C>T`, `NG_169445.1:g.441G>A`, `NM_000404.4:c.12C>T`, `NM_001039770.3:c.-464C>T`, `NM_001135602.3:c.12C>T`, `NM_001136238.2:c.-360C>T`, `NM_001317040.2:c.12C>T`, `NM_001393580.1:c.12C>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 -0.317, GERP -3.25 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.221**. 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 (gnomAD v4.1): grpmax **0.00401%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,818 in the highest group · 5/1,612,488 alleles overall — very rare (popmax 0.00401%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00401% | 24,939 |
| Admixed American | 0.00334% | 29,936 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-27.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-27 |

## 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, Mucopolysaccharidosis type 4B, Mucopolysaccharidosis type IVB (Morquio), MPS IVB, MORQUIO SYNDROME B, Mucopolysaccharidosis type IV B, Mucopolysaccharidosis Type IVB, Mucopolysaccharidosis Type IVB (Morquio B Disease).

## Similar variants {#similar}

Related GLB1 variant pages (same residue, condition, or type): [TMPPE p.Phe4Leu](/variant/tmppe-p-phe4leu), [TMPPE p.Phe4Val](/variant/tmppe-p-phe4val), [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 2026-10-06); 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 2940136). 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.*