Is MANBA p.Pro447Ser (c.1339C>T) pathogenic?

MANBA p.Pro447Ser (c.1339C>T) is classified Uncertain significance in MANBA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-29). AlphaMissense: likely benign (0.2924); Ultra-rare (popmax 0.0379%, eas); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Pro447Ser (c.1339C>T)?

MANBA p.Pro447Ser (c.1339C>T) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Pro447Ser (c.1339C>T) in the general population?

MANBA p.Pro447Ser (c.1339C>T) is ultra-rare (popmax 0.0379%, eas) (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.Pro447Ser (c.1339C>T)?

AlphaMissense predicts likely benign (score 0.2924) — an in-silico prediction, not a clinical call.

MANBA p.Pro447Ser

c.1339C>T · rs755785845 · VCV1393520

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2924 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

beta-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.2924	likely benign
REVEL	0.558	indeterminate
SaProt	LLR -8.73	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 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	27.5	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 0.0379% East Asian · 17/44,850 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00112% 18/1,606,784 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,638
European (non-Finnish)	8.52e-05%	1,173,418

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.Pro447Ser
Coding: c.1339C>T
MANE Select: NM_005908
dbSNP: rs755785845
Type: single nucleotide variant
Location: chr4:102664831 (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-pro447ser (accessed [today's date]).

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