Is MANBA p.Arg125= (c.375A>G) pathogenic?

MANBA p.Arg125= (c.375A>G) is classified Pathogenic in MANBA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-10). Very rare (popmax 0.00142%, nfe); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Arg125= (c.375A>G)?

MANBA p.Arg125= (c.375A>G) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Arg125= (c.375A>G) in the general population?

MANBA p.Arg125= (c.375A>G) is very rare (popmax 0.00142%, nfe) (gnomAD).

How is Beta-mannosidosis inherited?

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

MANBA p.Arg125=

c.375A>G · rs771587242 · VCV1680

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00142%, nfe)

Conditions

beta-mannosidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ1.00	donor gain · deltas
Pangolin	Δ0.88	gain · loss 0.81 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.3	GERP 0.17, phastCons 1
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00142% European (non-Finnish) · 16/1,127,686 alleles

Filtering AF 0.00084% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00068%

Overall 0.00122% 19/1,554,946 alleles · very rare exomes 17/1,402,714 · genomes 2/152,232 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,438
Finnishnot grpmax-eligible	0.00156%	63,936
European (non-Finnish)grpmax	0.00142%	70,481
African / African-American	0.00137%	73,230

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg125=
Coding: c.375A>G
MANE Select: NM_005908
dbSNP: rs771587242
Type: single nucleotide variant
Location: chr4:102723865 (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 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
MANBA c.549+1G>A Likely pathogenic ★★ same condition
MANBA c.550-1G>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-arg125 (accessed [today's date]).

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