Is MANBA p.Ala461Val (c.1382C>T) pathogenic?

MANBA p.Ala461Val (c.1382C>T) is classified Uncertain significance in MANBA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-02). AlphaMissense: ambiguous (0.5107); Very rare (popmax 0.00669%, eas); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Ala461Val (c.1382C>T)?

MANBA p.Ala461Val (c.1382C>T) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Ala461Val (c.1382C>T) in the general population?

MANBA p.Ala461Val (c.1382C>T) is very rare (popmax 0.00669%, 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.Ala461Val (c.1382C>T)?

AlphaMissense predicts ambiguous (score 0.5107) — an in-silico prediction, not a clinical call.

MANBA p.Ala461Val

c.1382C>T · rs775701916 · VCV1028958

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5107 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Conditions

beta-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.5107	ambiguous
REVEL	0.634	indeterminate
SaProt	LLR -11.56	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.81, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	23.1	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 0.00669% East Asian · 3/44,870 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00124% 20/1,609,440 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
Admixed American	0.005%	19,999
South Asian	0.0033%	30,328
Remaining individualsnot grpmax-eligible	0.00321%	31,175
African / African-American	0.00134%	74,792
European (non-Finnish)	0.00068%	146,982

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.Ala461Val
Coding: c.1382C>T
MANE Select: NM_005908
dbSNP: rs775701916
Type: single nucleotide variant
Location: chr4:102664788 (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.Ala461= Likely benign ★★ same residue
MANBA p.Ala461Thr 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-ala461val (accessed [today's date]).

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