Is MANBA p.Ser505Pro (c.1513T>C) pathogenic?

MANBA p.Ser505Pro (c.1513T>C) is classified Pathogenic in MANBA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2008-08-01). AlphaMissense: likely pathogenic (0.9684); Very rare (popmax 8.48e-05%, nfe); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Ser505Pro (c.1513T>C)?

MANBA p.Ser505Pro (c.1513T>C) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Ser505Pro (c.1513T>C) in the general population?

MANBA p.Ser505Pro (c.1513T>C) is very rare (popmax 8.48e-05%, 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.Ser505Pro (c.1513T>C)?

AlphaMissense predicts likely pathogenic (score 0.9684) — an in-silico prediction, not a clinical call.

MANBA p.Ser505Pro

c.1513T>C · rs121434334 · VCV1679

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9684 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.9684	likely pathogenic ✓ concordant with ClinVar · top 2% in MANBA
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -14.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	26.7	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 8.48e-05% European (non-Finnish) · 1/1,179,222 alleles

Overall 6.2e-05% 1/1,613,272 alleles · very rare exomes 1/1,460,946 · genomes 0/152,326 · 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.Ser505Pro
Coding: c.1513T>C
MANE Select: NM_005908
dbSNP: rs121434334
Type: single nucleotide variant
Location: chr4:102657873 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05
Residue 505: a UniProt-annotated variant site (in mansb; complete loss of enzyme activity); a UniProt-annotated variant site (in mansb; nearly 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.Ser505fs Pathogenic/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
MANBA c.378+1G>A Likely pathogenic ★★ same condition
MANBA c.549+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-ser505pro (accessed [today's date]).

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