# NM_005908.4(MANBA):c.2079A>G (p.Pro693=)

https://sugi.bio/variant/manba-p-pro693

## Summary

**MANBA p.Pro693= (c.2079A>G)** is classified **Likely benign** in MANBA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-29). Very rare (popmax 0.000934%, nfe); Associated with beta-mannosidosis.

**At a glance:** Likely benign · review: Single submitter · rsID rs148402714 · 1 submitter · 1 linked condition · very rare (popmax 0.000934%, nfe)

## For patients & families {#patients}

This is a change in the MANBA gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to beta-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) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MANBA is a diagnostic-grade gene on 7 Genomics England panels |

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

- Hearing impairment — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Recurrent respiratory infections — Very frequent (99-80%)
- Hypoplasia of the abdominal wall musculature — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000869/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MANBA](https://sugi.bio/atlas/gene/MANBA/) |
| Protein change (HGVS p.) | p.Pro693= |
| Coding change (HGVS c.) | c.2079A>G |
| MANE Select transcript | [NM_005908](https://www.ncbi.nlm.nih.gov/nuccore/NM_005908) |
| dbSNP | [rs148402714](https://www.ncbi.nlm.nih.gov/snp/rs148402714/) |
| Variant type | single nucleotide variant |
| Location | chr4:102635943-102635943 (GRCh38) |
| ClinVar | [VCV2996181](https://www.ncbi.nlm.nih.gov/clinvar/variation/2996181/) |

**All HGVS expressions:** `NC_000004.11:g.103557100T>C`, `NC_000004.12:g.102635943T>C`, `NG_012804.2:g.130052A>G`, `NM_005908.4:c.2079A>G`

## 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 -15.477, GERP -4.86 — fast-evolving / accelerated position
- CADD: **PHRED 1.507**. 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 (T>G, Δ0.64 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 **0.000934%** (nfe) · FAF95 0.000501% · FAF99 0.000366% · 11/1,178,282 in the highest group · 11/1,612,142 alleles overall — very rare (popmax 0.000934%, 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}

**MANBA** population constraint: LOEUF 0.826, pLI 2.4023e-10, missense-Z 0.063106. *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):

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

## Protein context {#protein}

Residue **693** lies in a UniProt-annotated variant site (in mansb; complete loss of enzyme activity).

AlphaFold model confidence (whole protein): pLDDT 96.05, 96% of residues very-high.

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

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


### Pathways affected {#pathways}

MANBA 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:** beta-mannosidase activity.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-29.

**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 | 2022-12-29 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Beta-D-mannosidosis, MANNOSIDOSIS, BETA A, LYSOSOMAL, BETA-MANNOSIDASE DEFICIENCY, LYSOSOMAL BETA-MANNOSIDASE DEFICIENCY, Beta-Mannosidosis.

## Similar variants {#similar}

Related MANBA variant pages (same residue, condition, or type): [MANBA c.1112+1G>T](/variant/manba-c-1112-plus-1g-t), [MANBA c.1231-1G>A](/variant/manba-c-1231-minus-1g-a), [MANBA c.1704+1G>T](/variant/manba-c-1704-plus-1g-t), [MANBA c.2158-2A>G](/variant/manba-c-2158-minus-2a-g), [MANBA c.273-1G>A](/variant/manba-c-273-minus-1g-a), [MANBA c.378+1G>A](/variant/manba-c-378-plus-1g-a), [MANBA c.549+1G>A](/variant/manba-c-549-plus-1g-a), [MANBA c.550-1G>A](/variant/manba-c-550-minus-1g-a).

### 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 2996181). 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.*