# NM_000181.4(GUSB):c.453C>T (p.Ala151=)

https://sugi.bio/variant/gusb-p-ala151

## Summary

**GUSB p.Ala151= (c.453C>T)** is classified **Likely benign** in GUSB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). Ultra-rare (popmax 0.028%, afr); Associated with mucopolysaccharidosis type 7.

**At a glance:** Likely benign · review: Single submitter · rsID rs144397476 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.028%, afr)

## For patients & families {#patients}

This is a change in the GUSB gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to mucopolysaccharidosis type 7.

*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) | Adolescent, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 13 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GUSB is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Mucopolysaccharidosis type 7** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Inguinal hernia — Very frequent (99-80%)
- Coarse facial features — Very frequent (99-80%)
- Lymphedema — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Umbilical hernia — Very frequent (99-80%)
- Ascites — Very frequent (99-80%)
- Abnormality of the pleura — Very frequent (99-80%)
- Recurrent respiratory infections — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007096/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GUSB](https://sugi.bio/atlas/gene/GUSB/) |
| Protein change (HGVS p.) | p.Ala151= |
| Coding change (HGVS c.) | c.453C>T |
| MANE Select transcript | [NM_000181](https://www.ncbi.nlm.nih.gov/nuccore/NM_000181) |
| dbSNP | [rs144397476](https://www.ncbi.nlm.nih.gov/snp/rs144397476/) |
| Variant type | single nucleotide variant |
| Location | chr7:65979855-65979855 (GRCh38) |
| ClinVar | [VCV2893579](https://www.ncbi.nlm.nih.gov/clinvar/variation/2893579/) |

**All HGVS expressions:** `NC_000007.13:g.65444842G>A`, `NC_000007.14:g.65979855G>A`, `NG_016197.1:g.7460C>T`, `NM_000181.4:c.453C>T`, `NM_001284290.2:c.453C>T`, `NM_001293104.2:c.12-314C>T`, `NM_001293105.2:c.67+369C>T`, `NR_120531.2:n.483C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.29) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.887, GERP -2.45 — fast-evolving / accelerated position
- CADD: **PHRED 9.393**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.07**, acceptor gain **0.29**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.29**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.028%** (afr) · FAF95 0.0188% · FAF99 0.0157% · 21/74,904 in the highest group · 40/1,613,132 alleles overall — ultra-rare (popmax 0.028%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.028% | 3,567 |
| Admixed American | 0.00501% | 19,978 |
| European (non-Finnish) | 0.00127% | 78,657 |
| South Asian | 0.0011% | 91,072 |

*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}

**GUSB** population constraint: LOEUF 0.871, pLI 3.6596e-11, missense-Z 1.451. *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):

- **mucopolysaccharidosis type 7** — Definitive (AR)

## Protein context {#protein}

Residue **151** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.35, 93% of residues very-high.

**2 experimental structure(s)** (PDB): [1BHG](https://www.rcsb.org/structure/1BHG), [3HN3](https://www.rcsb.org/structure/3HN3).

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

*Describes the biological roles of GUSB (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:** GUSB's established molecular role includes beta-glucuronidase activity. In Reactome, GUSB is annotated in disease pathway(s) including **MPS VII - Sly syndrome (CS/DS degradation)**, **MPS VII - Sly syndrome (Hyaluronan metabolism)**.

**Disease mechanism (Reactome):** GUSB loss or alteration is curated in [MPS VII - Sly syndrome (CS/DS degradation)](https://reactome.org/content/detail/R-HSA-9953080), [MPS VII - Sly syndrome (Hyaluronan metabolism)](https://reactome.org/content/detail/R-HSA-2206292).

### Pathways affected {#pathways}

GUSB participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [MPS VII - Sly syndrome (CS/DS degradation)](https://reactome.org/content/detail/R-HSA-9953080) | curated |
| ⚕ [MPS VII - Sly syndrome (Hyaluronan metabolism)](https://reactome.org/content/detail/R-HSA-2206292) | curated |
| [CS/DS degradation](https://reactome.org/content/detail/R-HSA-2024101) | curated |
| [Hyaluronan degradation](https://reactome.org/content/detail/R-HSA-2160916) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** beta-glucuronidase activity, signaling receptor binding, protein domain specific binding.

**Biological process:** hyaluronan catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-12.

**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 | 2024-03-12 |

## Associated conditions {#conditions}

[mucopolysaccharidosis type 7](https://sugi.bio/atlas/disease/mucopolysaccharidosis-type-7/).

**Reported phenotype names (ClinVar):** Mucopolysaccharidosis type 7, MPS VII, SLY SYNDROME, BETA-GLUCURONIDASE DEFICIENCY, GUSB DEFICIENCY.

## Similar variants {#similar}

Related GUSB variant pages (same residue, condition, or type): [GUSB p.Ala151Asp](/variant/gusb-p-ala151asp), [GUSB c.1244+1G>A](/variant/gusb-c-1244-plus-1g-a), [GUSB c.581+1G>A](/variant/gusb-c-581-plus-1g-a), [GUSB c.724+1G>T](/variant/gusb-c-724-plus-1g-t), [GUSB p.Ala619Val](/variant/gusb-p-ala619val), [GUSB p.Arg110Ter](/variant/gusb-p-arg110ter), [GUSB p.Arg167Ter](/variant/gusb-p-arg167ter), [GUSB p.Arg216Trp](/variant/gusb-p-arg216trp).

### 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 2026-07-14); 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 2893579). 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.*