Is MANBA p.Trp412fs (c.1234dup) pathogenic?

MANBA p.Trp412fs (c.1234dup) is classified Pathogenic in MANBA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-20). Very rare (popmax 0.00134%, afr); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Trp412fs (c.1234dup)?

MANBA p.Trp412fs (c.1234dup) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Trp412fs (c.1234dup) in the general population?

MANBA p.Trp412fs (c.1234dup) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Beta-mannosidosis inherited?

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

MANBA p.Trp412fs

c.1234dup · rs1731366707 · VCV2719776

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

beta-mannosidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 0.68, phastCons 1
Overall
CADD	34.0	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 0.00134% African / African-American · 1/74,846 alleles

Overall 0.000657% 1/152,146 alleles · very rare

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.Trp412fs
Coding: c.1234dup
MANE Select: NM_005908
dbSNP: rs1731366707
Type: Duplication
Location: chr4:102669045 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05

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.Trp412Ter Pathogenic ★ same residue
MANBA p.Asp191_Trp192insTer Pathogenic ★★ same condition
MANBA p.Ser726fs Pathogenic/Likely pathogenic ★★ same condition
MANBA c.2416-20dup Benign/Likely benign ★★ same condition
MANBA p.Arg613fs Pathogenic ★ same condition
MANBA p.Gln261fs Pathogenic ★ same condition
MANBA p.Glu672Ter Likely pathogenic ★ same condition
MANBA p.Ile201fs 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-trp412fs (accessed [today's date]).

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