Is MANBA p.Pro784Arg (c.2351C>G) pathogenic?

MANBA p.Pro784Arg (c.2351C>G) is classified Benign/Likely benign in MANBA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1895); Low-frequency (popmax 3.8%, afr); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Pro784Arg (c.2351C>G)?

MANBA p.Pro784Arg (c.2351C>G) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Pro784Arg (c.2351C>G) in the general population?

MANBA p.Pro784Arg (c.2351C>G) is low-frequency (popmax 3.8%, afr) (gnomAD).

How is Beta-mannosidosis inherited?

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

What do computational predictors say about MANBA p.Pro784Arg (c.2351C>G)?

AlphaMissense predicts likely benign (score 0.1895) — an in-silico prediction, not a clinical call.

MANBA p.Pro784Arg

c.2351C>G · rs116340501 · VCV347081

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1895 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.8%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

beta-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.1895	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.8% African / African-American · 2,851/75,038 alleles

Filtering AF 3.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.64%

Overall 0.196% 3,164/1,614,130 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.8%	26
Admixed American	0.217%	462
Remaining individualsnot grpmax-eligible	0.213%	470
Middle Eastern	0.116%	865
European (non-Finnish)	0.00347%	28,781
South Asian	0.0022%	45,536

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.Pro784Arg
Coding: c.2351C>G
MANE Select: NM_005908
dbSNP: rs116340501
Type: single nucleotide variant
Location: chr4:102634852 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05
Residue 784: 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.Pro784Leu Uncertain significance ★★ ⚠ same residue
MANBA p.Pro784= Likely benign ★ same residue
MANBA p.Pro784fs Likely 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

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-pro784arg (accessed [today's date]).

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