Is MANBA p.Ser727Phe (c.2180C>T) pathogenic?

MANBA p.Ser727Phe (c.2180C>T) is classified Conflicting classifications of pathogenicity in MANBA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1888); Rare (popmax 0.63%, afr); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Ser727Phe (c.2180C>T)?

MANBA p.Ser727Phe (c.2180C>T) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Ser727Phe (c.2180C>T) in the general population?

MANBA p.Ser727Phe (c.2180C>T) is rare (popmax 0.63%, 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.Ser727Phe (c.2180C>T)?

AlphaMissense predicts likely benign (score 0.1888) — an in-silico prediction, not a clinical call.

MANBA p.Ser727Phe

c.2180C>T · rs147437033 · VCV1028960

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1888 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.63%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.1888	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	21.7	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 0.63% African / African-American · 473/75,052 alleles

Filtering AF 0.583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.565%

Overall 0.0336% 543/1,614,158 alleles · rare exomes 269/1,461,840 · genomes 274/152,318 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.63%	159
Remaining individualsnot grpmax-eligible	0.0464%	2,156
Middle Eastern	0.033%	3,031
Admixed American	0.02%	5,002
South Asian	0.00659%	15,179
European (non-Finnish)	0.00178%	56,191

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.Ser727Phe
Coding: c.2180C>T
MANE Select: NM_005908
dbSNP: rs147437033
Type: single nucleotide variant
Location: chr4:102635023 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05
Residue 727: 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.Ser727= Likely benign ★ same residue
MANBA p.Ser727Thr Uncertain significance ★ ⚠ 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-ser727phe (accessed [today's date]).

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