Is MANBA p.Pro784Leu (c.2351C>T) pathogenic?

MANBA p.Pro784Leu (c.2351C>T) is classified Uncertain significance in MANBA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.199); Very rare (popmax 0.00339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MANBA p.Pro784Leu (c.2351C>T)?

MANBA p.Pro784Leu (c.2351C>T) is associated with Inborn genetic diseases, beta-mannosidosis (ClinVar).

How common is MANBA p.Pro784Leu (c.2351C>T) in the general population?

MANBA p.Pro784Leu (c.2351C>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about MANBA p.Pro784Leu (c.2351C>T)?

AlphaMissense predicts likely benign (score 0.199) — an in-silico prediction, not a clinical call.

MANBA p.Pro784Leu

c.2351C>T · rs116340501 · VCV1377287

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.199	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -8.21	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	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00339% European (non-Finnish) · 40/1,180,018 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00273% 44/1,614,132 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,500
East Asian	0.00223%	44,876
South Asian	0.0022%	45,536
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Pro784Leu
Coding: c.2351C>T
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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: beta-mannosidosis

Similar variants

MANBA p.Pro784Arg Benign/Likely benign ★★ 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-pro784leu (accessed [today's date]).

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