Is MANBA p.Val514fs (c.1540_1541del) pathogenic?

MANBA p.Val514fs (c.15401541del) is classified Pathogenic/Likely pathogenic in MANBA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-13). Very rare (popmax 0.00746%, nfe); Associated with MANBA-related disorder.

What condition is associated with MANBA p.Val514fs (c.1540_1541del)?

MANBA p.Val514fs (c.1540_1541del) is associated with MANBA-related disorder, beta-mannosidosis (ClinVar).

How common is MANBA p.Val514fs (c.1540_1541del) in the general population?

MANBA p.Val514fs (c.1540_1541del) is very rare (popmax 0.00746%, nfe) (gnomAD).

MANBA p.Val514fs

c.1540_1541del · rs775574131 · VCV542166

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Conditions

MANBA-related disorder

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 12 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.87	GERP -2.9
Overall
CADD	25.4	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 0.00746% European (non-Finnish) · 88/1,179,890 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00551% 89/1,613,896 alleles · very rare exomes 88/1,461,672 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00746%	13,408
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Val514fs
Coding: c.1540_1541del
MANE Select: NM_005908
dbSNP: rs775574131
Type: Deletion
Location: chr4:102657845 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05
Residue 514: 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

MANBA-related disorder

Also linked: beta-mannosidosis

Similar variants

MANBA p.Asn578fs Pathogenic ★★ same condition
MANBA p.Leu306fs Pathogenic/Likely pathogenic ★★ same condition
MANBA p.Lys479fs Pathogenic/Likely pathogenic ★★ same condition
MANBA p.Tyr485fs Pathogenic ★★ same condition
MANBA c.2416-10del Benign ★★ same condition
MANBA c.273-3del Benign/Likely benign ★★ same condition
MANBA p.Ala549fs Pathogenic ★ same condition
MANBA p.Ala777fs 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-val514fs (accessed [today's date]).

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