Is MANBA p.Ser139Pro (c.415T>C) pathogenic?

MANBA p.Ser139Pro (c.415T>C) is classified Uncertain significance in MANBA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-09). AlphaMissense: likely pathogenic (0.6086); Very rare (popmax 0.00102%, nfe); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Ser139Pro (c.415T>C)?

MANBA p.Ser139Pro (c.415T>C) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Ser139Pro (c.415T>C) in the general population?

MANBA p.Ser139Pro (c.415T>C) is very rare (popmax 0.00102%, nfe) (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.Ser139Pro (c.415T>C)?

AlphaMissense predicts likely pathogenic (score 0.6086) — an in-silico prediction, not a clinical call.

MANBA p.Ser139Pro

c.415T>C · rs1007859913 · VCV2183430

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.6086	likely pathogenic
REVEL	0.197	benign-leaning
SaProt	LLR -11.89	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.26	GERP -1.4, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	14.62	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 0.00102% European (non-Finnish) · 12/1,180,006 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000743% 12/1,614,046 alleles · very rare exomes 11/1,461,852 · genomes 1/152,194 · joint denominator

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.Ser139Pro
Coding: c.415T>C
MANE Select: NM_005908
dbSNP: rs1007859913
Type: single nucleotide variant
Location: chr4:102723005 (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-ser139pro (accessed [today's date]).

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