Is MAN2B1 p.Pro282Ser (c.844C>T) pathogenic?

MAN2B1 p.Pro282Ser (c.844C>T) is classified Conflicting classifications of pathogenicity in MAN2B1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0947); Rare (popmax 0.429%, nfe); Associated with alpha-mannosidosis.

What condition is associated with MAN2B1 p.Pro282Ser (c.844C>T)?

MAN2B1 p.Pro282Ser (c.844C>T) is associated with alpha-mannosidosis (ClinVar).

How common is MAN2B1 p.Pro282Ser (c.844C>T) in the general population?

MAN2B1 p.Pro282Ser (c.844C>T) is rare (popmax 0.429%, 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.Pro282Ser (c.844C>T)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

MAN2B1 p.Pro282Ser

c.844C>T · rs45576136 · VCV558862

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.429%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

alpha-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -10.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -0.48, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.03 · regional, not allelic
Overall
CADD	19.56	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 0.429% European (non-Finnish) · 5,067/1,179,942 alleles

Filtering AF 0.42% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.415%

Overall 0.365% 5,887/1,613,946 alleles · rare exomes 5,460/1,461,816 · genomes 427/152,130 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.429%	233
Admixed American	0.422%	237
Remaining individualsnot grpmax-eligible	0.373%	268
Finnishnot grpmax-eligible	0.352%	284
Ashkenazi Jewishnot grpmax-eligible	0.132%	759
African / African-American	0.0867%	1,153
Middle Eastern	0.0495%	2,020
South Asian	0.0022%	45,539

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.Pro282Ser
Coding: c.844C>T
MANE Select: NM_000528
dbSNP: rs45576136
Type: single nucleotide variant
Location: chr19:12663382 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.78
Residue 282: a UniProt-annotated variant site (in mansa); a UniProt-annotated variant site (in)

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 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
MAN2B1 c.1527+2T>G Pathogenic ★★ same condition
MAN2B1 c.1528-1G>A Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1528-1G>T Likely pathogenic ★★ same condition
MAN2B1 c.159+2T>C 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-pro282ser (accessed [today's date]).

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