Is MANBA p.Arg366Pro (c.1097G>C) pathogenic?

MANBA p.Arg366Pro (c.1097G>C) is classified Uncertain significance in MANBA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-31). AlphaMissense: likely pathogenic (0.8798); Absent from gnomAD v4.1; Associated with beta-mannosidosis.

What condition is associated with MANBA p.Arg366Pro (c.1097G>C)?

MANBA p.Arg366Pro (c.1097G>C) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Arg366Pro (c.1097G>C) in the general population?

MANBA p.Arg366Pro (c.1097G>C) is absent from gnomAD v4.1 (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.Arg366Pro (c.1097G>C)?

AlphaMissense predicts likely pathogenic (score 0.8798) — an in-silico prediction, not a clinical call.

MANBA p.Arg366Pro

c.1097G>C · rs757289997 · VCV2104718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8798 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

beta-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.8798	likely pathogenic · top 10% in MANBA
REVEL	0.631	indeterminate
SaProt	LLR -16.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.86, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MANBA
Protein: p.Arg366Pro
Coding: c.1097G>C
MANE Select: NM_005908
dbSNP: rs757289997
Type: single nucleotide variant
Location: chr4:102673934 (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 p.Arg366Ter Pathogenic ★ same residue
MANBA p.Arg366= Likely benign ★ 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
MANBA c.378+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-arg366pro (accessed [today's date]).

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