Is MANBA p.Arg550Ter (c.1648C>T) pathogenic?

MANBA p.Arg550Ter (c.1648C>T) is classified Pathogenic/Likely pathogenic in MANBA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-24). Very rare (popmax 0.00534%, afr); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Arg550Ter (c.1648C>T)?

MANBA p.Arg550Ter (c.1648C>T) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Arg550Ter (c.1648C>T) in the general population?

MANBA p.Arg550Ter (c.1648C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Beta-mannosidosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MANBA p.Arg550Ter

c.1648C>T · rs780068572 · VCV2896556

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

beta-mannosidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 17
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP -0.3, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,858 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00136% 22/1,613,662 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,715
East Asian	0.00446%	22,440
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.0011%	90,755
South Asian	0.0011%	91,068

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MANBA
Protein: p.Arg550Ter
Coding: c.1648C>T
MANE Select: NM_005908
dbSNP: rs780068572
Type: single nucleotide variant
Location: chr4:102657738 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05
Residue 550: a disulfide bond; a UniProt-annotated variant site (in mansb; complete loss of enzyme activity)

Full MANBA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

beta-mannosidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Beta-mannosidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

MANBA p.Arg550Gln Uncertain significance ★★ ⚠ same residue
MANBA p.Arg550fs Pathogenic ★ same residue
MANBA c.1112+1G>T Likely pathogenic ★★ same condition
MANBA c.1231-1G>A Likely pathogenic ★★ same condition
MANBA c.1704+1G>T Likely pathogenic ★★ same condition
MANBA c.2158-2A>G Pathogenic ★★ same condition
MANBA c.273-1G>A Likely pathogenic ★★ same condition
MANBA c.378+1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/manba-p-arg550ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown