# NM_000528.4(MAN2B1):c.1662C>T (p.Ser554=)

https://sugi.bio/variant/man2b1-p-ser554

## Summary

**MAN2B1 p.Ser554= (c.1662C>T)** is classified **Likely benign** in MAN2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-11). Very rare (popmax 0.000169%, nfe); Associated with alpha-mannosidosis.

**At a glance:** Likely benign · review: Single submitter · rsID rs755140505 · 1 submitter · 1 linked condition · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the MAN2B1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to alpha-mannosidosis.

*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, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 21 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MAN2B1 is a diagnostic-grade gene on 14 Genomics England panels |

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

- Macroglossia — Very frequent (99-80%)
- Coarse facial features — Very frequent (99-80%)
- Hearing impairment — Very frequent (99-80%)
- Cataract — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Splenomegaly — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006968/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MAN2B1](https://sugi.bio/atlas/gene/MAN2B1/) |
| Protein change (HGVS p.) | p.Ser554= |
| Coding change (HGVS c.) | c.1662C>T |
| MANE Select transcript | [NM_000528](https://www.ncbi.nlm.nih.gov/nuccore/NM_000528) |
| dbSNP | [rs755140505](https://www.ncbi.nlm.nih.gov/snp/rs755140505/) |
| Variant type | single nucleotide variant |
| Location | chr19:12655862-12655862 (GRCh38) |
| ClinVar | [VCV1084727](https://www.ncbi.nlm.nih.gov/clinvar/variation/1084727/) |

**All HGVS expressions:** `NC_000019.10:g.12655862G>A`, `NC_000019.9:g.12766676G>A`, `NG_008318.1:g.15916C>T`, `NM_000528.4:c.1662C>T`, `NM_001173498.2:c.1659C>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 1.477, GERP -0.708, phastCons 0.138 — weakly conserved position
- CADD: **PHRED 6.749**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.28 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,000 in the highest group · 2/1,613,808 alleles overall — very rare (popmax 0.000169%, nfe).

*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}

**MAN2B1** population constraint: LOEUF 0.898, pLI 6.3922e-24, missense-Z 0.90018. *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):

- **alpha-mannosidosis** — Definitive (AR)

## Protein context {#protein}

Residue **554** lies in a UniProt-annotated variant site (in mansa); a UniProt-annotated variant site (in mansa; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 91.78, 86% of residues very-high.

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

*Describes the biological roles of MAN2B1 (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:** MAN2B1's established molecular role includes alpha-mannosidase activity.


### Pathways affected {#pathways}

MAN2B1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Lysosomal oligosaccharide catabolism](https://reactome.org/content/detail/R-HSA-8853383) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** alpha-mannosidase activity.

**Biological process:** glycoprotein catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-10-11.

**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 | 2020-10-11 |

## Associated conditions {#conditions}

[alpha-mannosidosis](https://sugi.bio/atlas/disease/alpha-mannosidosis/).

**Reported phenotype names (ClinVar):** Deficiency of alpha-mannosidase, Mannosidosis, alpha-, types I and II, Alpha-Mannosidosis, LYSOSOMAL ALPHA-D-MANNOSIDASE DEFICIENCY.

## Similar variants {#similar}

Related MAN2B1 variant pages (same residue, condition, or type): [MAN2B1 p.Ser554Gly](/variant/man2b1-p-ser554gly), [MAN2B1 c.1026+2T>G](/variant/man2b1-c-1026-plus-2t-g), [MAN2B1 c.1109+1G>C](/variant/man2b1-c-1109-plus-1g-c), [MAN2B1 c.1527+1G>A](/variant/man2b1-c-1527-plus-1g-a), [MAN2B1 c.1527+1G>T](/variant/man2b1-c-1527-plus-1g-t), [MAN2B1 c.1527+2T>G](/variant/man2b1-c-1527-plus-2t-g), [MAN2B1 c.1528-1G>A](/variant/man2b1-c-1528-minus-1g-a), [MAN2B1 c.1528-1G>T](/variant/man2b1-c-1528-minus-1g-t).

### 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 1084727). 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.*