Is MAN2B1 p.Gly485Ala (c.1454G>C) pathogenic?

MAN2B1 p.Gly485Ala (c.1454G>C) is classified Uncertain significance in MAN2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-02). AlphaMissense: likely benign (0.1756); Very rare (popmax 8.48e-05%, nfe); Associated with alpha-mannosidosis.

What condition is associated with MAN2B1 p.Gly485Ala (c.1454G>C)?

MAN2B1 p.Gly485Ala (c.1454G>C) is associated with alpha-mannosidosis (ClinVar).

How common is MAN2B1 p.Gly485Ala (c.1454G>C) in the general population?

MAN2B1 p.Gly485Ala (c.1454G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Alpha-mannosidosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MAN2B1 p.Gly485Ala (c.1454G>C)?

AlphaMissense predicts likely benign (score 0.1756) — an in-silico prediction, not a clinical call.

MAN2B1 p.Gly485Ala

c.1454G>C · rs373553609 · VCV1515981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1756 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alpha-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.1756	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -10.06	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 2.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.03 · regional, not allelic
Overall
CADD	17.38	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) · 1/1,179,906 alleles

Overall 6.2e-05% 1/1,613,252 alleles · very rare exomes 1/1,460,918 · genomes 0/152,334 · 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: MAN2B1
Protein: p.Gly485Ala
Coding: c.1454G>C
MANE Select: NM_000528
dbSNP: rs373553609
Type: single nucleotide variant
Location: chr19:12657022 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.78
Residue 485: a UniProt-annotated variant site (in mansa); a UniProt-annotated variant site (in mansa; uncertain significance)

Full MAN2B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

alpha-mannosidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alpha-mannosidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

MAN2B1 p.Gly485Ser Uncertain significance ★★ ⚠ same residue
MAN2B1 p.Gly485Val Uncertain significance ★ ⚠ same residue
MAN2B1 p.Gly485= Likely benign ★ same residue
MAN2B1 p.Gly485fs Likely pathogenic ★ same residue
MAN2B1 c.1026+2T>G Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1109+1G>C Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1527+1G>A Likely pathogenic ★★ same condition
MAN2B1 c.1527+1G>T Pathogenic/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/man2b1-p-gly485ala (accessed [today's date]).

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